Browsing by Subject "OSTEOPOROSIS"

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  • GEMSTONE Working Grp 3 COST Action; Formosa, Melissa M.; Bergen, Dylan J. M.; Gregson, Celia L.; Mäkitie, Outi (2021)
    Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.
  • 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.
  • Mäkitie, Riikka E.; Kämpe, Anders; Costantini, Alice; Alm, Jessica J.; Magnusson, Per; Mäkitie, Outi (2020)
    Recent advancements in genetic research have uncovered new forms of monogenic osteoporosis, expanding our understanding of the molecular pathways regulating bone health. Despite active research, knowledge on the pathomechanisms, disease-specific biomarkers, and optimal treatment in these disorders is still limited. Mutations in WNT1, encoding a WNT/beta-catenin pathway ligand WNT1, and PLS3, encoding X chromosomally inherited plastin 3 (PLS3), both result in early-onset osteoporosis with prevalent fractures and disrupted bone metabolism. However, despite marked skeletal pathology, conventional bone markers are usually normal in both diseases. Our study aimed to identify novel bone markers in PLS3 and WNT1 osteoporosis that could offer diagnostic potential and shed light on the mechanisms behind these skeletal pathologies. We measured several parameters of bone metabolism, including serum dickkopf-1 (DKK1), sclerostin, and intact and C-terminal fibroblast growth factor 23 (FGF23) concentrations in 17 WNT1 and 14 PLS3 mutation-positive subjects. Findings were compared with 34 healthy mutation-negative subjects from the same families. Results confirmed normal concentrations of conventional metabolic bone markers in both groups. DKK1 concentrations were significantly elevated in PLS3 mutation-positive subjects compared with WNT1 mutation-positive subjects (p <.001) or the mutation-negative subjects (p = .002). Similar differences were not seen in WNT1 subjects. Sclerostin concentrations did not differ between any groups. Both intact and C-terminal FGF23 were significantly elevated in WNT1 mutation-positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects. Our results indicate a link between PLS3 and DKK1 and WNT1 and FGF23 in bone metabolism. The normal sclerostin and DKK1 levels in patients with impaired WNT signaling suggest another parallel regulatory mechanism. These findings provide novel information on the molecular networks in bone. Extended studies are needed to investigate whether these biomarkers offer diagnostic value or potential as treatment targets in osteoporosis. (c) 2020 American Society for Bone and Mineral Research.
  • Kosola, Jussi; Kaipia, Antti; Laitinen, Minna K.; Nieminen, Jyrki (2017)
    Purpose One-third of hip fractures occur in men. The causes underlying hip fractures in men differ from those in women and include alcohol abuse. This retrospective register study evaluated the trends and results associated with different surgical treatment methods for nondisplaced and displaced femoral neck fractures in male patients with alcohol dependence syndrome. Methods Men with hip fractures were identified from a local district hospital database. Alcohol dependence syndrome was identified as a diagnosis in medical records. Results For displaced fractures, implant survival after total hip arthroplasty was significantly lower compared to hemiarthroplasty. For nondisplaced fractures, implant survival of cannulated screws was significantly lower compared to sliding hip screws. Overall patient survival for males with alcohol dependence syndrome with hip fracture was 62% at 1 year and 49% at 2 years. Patient survival in this population did not differ between displaced and nondisplaced fractures or among different surgical methods. Conclusion Patients with alcoholism who had documented evidence of alcohol dependence syndrome represented nearly half of patients
  • Lehtovirta, S.; Mäkitie, R. E.; Casula, V.; Haapea, M.; Niinimäki, J.; Niinimäki, T.; Peuna, A.; Lammentausta, E.; Mäkitie, O.; Nieminen, M.T. (2019)
    Objective: WNT signaling is of key importance in chondrogenesis and defective WNT signaling may contribute to the pathogenesis of osteoarthritis and other cartilage diseases. Biochemical composition of articular cartilage in patients with aberrant WNT signaling has not been studied. Our objective was to assess the knee articular cartilage in WNT1 mutation-positive individuals using a 3.0T MRI unit to measure cartilage thickness, relaxation times, and texture features. Design: Cohort comprised mutation-positive (N = 13; age 17-76 years) and mutation-negative (N = 13; 16-77 years) subjects from two Finnish families with autosomal dominant WNT1 osteoporosis due to a heterozygous missense mutation c.652T>G (p.C218G) in WNT1. All subjects were imaged with a 3.0T MRI unit and assessed for cartilage thickness, T2 and T1 rho relaxation times, and T2 texture features contrast, dissimilarity and homogeneity of T2 relaxation time maps in six regions of interest (ROIs) in the tibiofemoral cartilage. Results: All three texture features showed opposing trends with age between the groups in the medial tibiofemoral cartilage (P = 0.020-0.085 for the difference of the regression coefficients), the mutation-positive individuals showing signs of cartilage preservation. No significant differences were observed in the lateral tibiofemoral cartilage. Cartilage thickness and means of T2 relaxation time did not differ between groups. Means of T1r relaxation time were significantly different in one ROI but the regression analysis displayed no differences. Conclusions: Our results show less age-related cartilage deterioration in the WNT1 mutation-positive than the mutation-negative subjects. This suggests, that the WNT1 mutation may alter cartilage turnover and even have a potential cartilage-preserving effect. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
  • Itkonen, Suvi T.; Rita, Hannu J.; Saarnio, Elisa M.; Kemi, Virpi E.; Karp, Heini J.; Kärkkäinen, Merja; Pekkinen, Minna H.; Laitinen, E. Kalevi; Risteli, Juha; Koivula, Marja-Kaisa; Sievanen, Harri; Lamberg-Allardt, Christel J. E. (2017)
    High dietary phosphorus (P) intake has acute negative effects on calcium (Ca) and bone metabolism, but long-term clinical data are contradictory. We hypothesized that high P intake is associated with impaired bone health as suggested by earlier short-term studies on bone metabolism. In this cross-sectional study, we investigated associations between dietary P intake, bone traits in the radius and tibia, and bone turnover in a population-based sample of 37- to 47-year-old Caucasian premenopausal women (n = 333) and men (n = 179) living in Southern Finland (60 degrees N). We used various regression models in an "elaboration approach" to elucidate the role of P intake in bone traits and turnover. The addition of relevant covariates to the models mainly removed the significance of P intake as a determinant of bone traits. In the final regression model (P intake, weight, height, age, Ca intake, serum 25-hydroxyvitamin D, physical activity, smoking, contraceptive use in women), P intake was slightly positively associated only with bone mineral content and cross-sectional cortical bone area in the tibia of men. Among women, inclusion of Ca removed all existing significance in the crude models for any bone trait. In women P intake was negatively associated with the bone formation marker serum intact pro-collagen type I amino-terminal propeptide, whereas no association was present between P intake and bone turnover in men. In conclusion, these findings disagree with the hypothesis; P intake was not deleteriously associated with bone traits; however, P intake may negatively contribute to bone formation among women. (C) 2016 Elsevier Inc. All rights reserved.
  • Costantini, Alice; Mäkitie, Riikka E.; Hartmann, Markus A.; Fratzl-Zelman, Nadja; Zillikens, M. Carola; Kornak, Uwe; Soe, Kent; Mäkitie, Outi (2022)
    Early-onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged
  • GBD 2019 Fracture Collaborators; Wu, Ai-Min; Bisignano, Catherine; James, Spencer L.; Meretoja, Tuomo J. (2021)
    Background Bone fractures are a global public health issue; however, to date, no comprehensive study of their incidence and burden has been done. We aimed to measure the global, regional, and national incidence, prevalence, and years lived with disability (YLDs) of fractures from 1990 to 2019. Methods Using the framework of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we compared numbers and age-standardised rates of global incidence, prevalence, and YLDs of fractures across the 21 GBD regions and 204 countries and territories, by age, sex, and year, from 1990 to 2019. We report estimates with 95% uncertainty intervals (UIs). Findings Globally, in 2019, there were 178 million (95% UI 162-196) new fractures (an increase of 33.4% [30.1-37.0] since 1990), 455 million (428-484) prevalent cases of acute or long-term symptoms of a fracture (an increase of 70.1% [67.5-72.5] since 1990), and 25.8 million (17.8-35.8) YLDs (an increase of 65.3% [62.4-68.0] since 1990). The age-standardised rates of fractures in 2019 were 2296.2 incident cases (2091.1-2529.5) per 100 000 population (a decrease of 9.6% [8.1-11.1] since 1990), 5614.3 prevalent cases (5286.1-5977.5) per 100 000 population (a decrease of 6.7% [5.7-7.6] since 1990), and 319.0 YLDs (220.1-442.5) per 100 000 population (a decrease of 8.4% [7.2-9.5] since 1990). Lower leg fractures of the patella, tibia or fibula, or ankle were the most common and burdensome fracture in 2019, with an age-standardised incidence rate of 419.9 cases (345.8-512.0) per 100 000 population and an age-standardised rate of YLDs of 190.4 (125.0-276.9) per 100 000 population. In 2019, age-specific rates of fracture incidence were highest in the oldest age groups, with, for instance, 15 381.5 incident cases (11 245.3-20 651.9) per 100 000 population in those aged 95 years and older. Interpretation The global age-standardised rates of incidence, prevalence, and YLDs for fractures decreased slightly from 1990 to 2019, but the absolute counts increased substantially. Older people have a particularly high risk of fractures, and more widespread injury-prevention efforts and access to screening and treatment of osteoporosis for older individuals should help to reduce the overall burden. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
  • Lundbom, Jesper; Bierwagen, Alessandra; Bodis, Kalman; Apostolopoulou, Maria; Szendroedi, Julia; Müssig, Karsten; Hwang, Jong-Hee; Roden, Michael (2019)
    Objectives There is a discrepancy between studies suggesting that higher bone marrow fat saturation is associated with impaired health, and studies suggesting that erythropoiesis increases red bone marrow (RBM) fat saturation in young healthy individuals. Here, we seeked to elucidate these discrepancies by using long TE magnetic resonance spectroscopy (MRS) to study both yellow bone marrow (YBM) and RBM in the femur of healthy volunteers. Materials and methods Thirty-three young healthy volunteers (17 females), age range 20-31 years, underwent long TE H-1 MRS at 3.0 T of RBM and YBM fat composition in the left femur. The water content of the bone marrow depots was measured using short TE MRS. Results The female participants displayed a lower unsaturation in the sampled RBM volume (RBMV) than the males (P <0.01) without displaying a concomitant difference in YBM (P = 0.42). They also showed a higher water content and broader spectral linewidths in RBM (P = 0.04). The water content in RBM strongly associated with broader spectral linewidths (R = 0.887, P MUCH LESS-THAN 0.01) and inversely with RBMV fat unsaturation (R = - 0.365, P = 0.04). Discussion These results partly support the notion that females display higher rate of erythropoiesis and lower fat unsaturation in RBM.
  • Costantini, Alice; Kekalainen, Paivi; Makitie, Riikka E.; Makitie, Outi (2017)
    WNT signaling is a key regulator of bone metabolism and its increased or decreased activity leads to skeletal disorders. Here we describe two patients with high bone mass (HBM) caused by novel mutations in two different WNT pathway components. The first patient is a 53-year-old male with HBM. He was diagnosed at adult age based on significantly increased bone mineral density (BMD). He has undergone several surgeries due to excessive bone in ear canals, bilateral jaw exostoses and mandibular tori. Radiographs show severe cortical thickening of cranial and long bones. Sanger sequencing identified a novel heterozygous mutation c. 592A> T (p. N198Y) in LRP5 (Low-density lipoprotein receptor-related protein 5). The second patient, an adolescent female, was diagnosed with skeletal dysplasia in early childhood. She had macrocephaly (head circumference +6.0 SD), facial dysmorphism, delayed motor development, laryngomalasia and epilepsy. Radiographic findings were consistent with osteopathia striata with cranial sclerosis. A novel heterozygous frameshift mutation c. 655del (p. E219Rfs* 63) in AMER1 (APC Membrane Recruiting Protein 1) was identified. Although both mutations are predicted to lead to increased WNT signaling with a consequent increase in bone formation, the resulting phenotypes are different; cranial sclerosis versus macrocephaly, long bone cortical thickening versus vertical striations and discordant neurological development. This report underscores the diversity of genotypes and phenotypes of HBM and facilitates their differential diagnosis. (C) 2017 Elsevier Masson SAS. All rights reserved.
  • Mäkitie, Riikka E.; Niinimaki, Tuukka; Nieminen, Miika T.; Schalin-Jantti, Camilla; Niinimaki, Jaakko; Makitie, Outi (2017)
    Background: WNT signaling plays a major role in bone and cartilage metabolism. Impaired WNT/beta-catenin signaling leads to early-onset osteoporosis, but specific features in bone and other tissues remain inadequately characterized. We have identified two large Finnish families with early-onset osteoporosis due to a heterozygous WNT1 mutation c.652T>G, p.C218G. This study evaluated the impact of impaired WNT/beta-catenin signaling on spinal structures. Methods: Altogether 18 WNT1 mutation-positive (age range 11-76 years, median 49 years) and 14 mutation negative subjects (10-77 years, median 43 years) underwent magnetic resonance imaging (MRI) of the spine. The images were reviewed for spinal alignment, vertebral compression fractures, intervertebral disc changes and possible endplate deterioration. The findings were correlated with clinical data. Results: Vertebral compression fractures were present in 78% (7/9) of those aged over 50 years but were not seen in younger mutation-positive subjects. All those with fractures had several severely compressed vertebrae. Altogether spinal compression fractures were present in 39% of those with a WNT1 mutation. Only 14% (2/14) mutation -negative subjects had one mild compressed vertebra each. The mutation-positive subjects had a higher mean spinal deformity index (4.0 +/- 7.3 vs 0.0 +/- 0.4) and more often increased thoracic kyphosis (Z-score > + 2.0 in 33% vs 0%). Further, they had more often Schmorl nodes (61% vs 36%), already in adolescence, and their intervertebral discs were enlarged. Conclusion: Compromised WNT signaling introduces severe and progressive changes to the spinal structures. Schmorl nodes are prevalent even at an early age and increased thoracic kyphosis and compression fractures become evident after the age of 50 years. Therapies targeting the WNT pathway may be an effective way to prevent spinal pathology not only in those harboring a mutation but also in the general population with similar pathology. (C) 2017 Elsevier Inc. All rights reserved.
  • Salooja, Nina; Greinix, Hildegaard; Ruutu, Tapani; van der Werf, Steffie; van Biezen, Anja; Lawitschka, Anita; Basak, Grzegorz; Duarte, Rafael (2020)
    Reduced bone mineral density (BMD) is a well-recognized complication of hematopoietic cell transplantation (HCT), with significant drops in BMD occurring within the first 12 months after HCT. Guidance on identifying and managing this complication is available in several published guidelines. In this study, we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation (EBMT). A questionnaire about bone health was sent to all registered centers, and responses were received from 99 centers in 25 countries (52%) currently registered with the EBMT. Our data highlight considerable heterogeneity in practices across European centers in relation to investigations, management, and use of guidelines. Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders. (c) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
  • Korhonen, Marko T.; Kujala, Urho M.; Kettunen, Jyrki; Korhonen, Olga V.; Kaprio, Jaakko; Sarna, Seppo; Törmäkangas, Timo (2022)
    Maintenance of vigorous exercise habits from young to old age is considered protective against hip fractures, but data on fracture risk in lifelong vigorous exercisers are lacking. This longitudinal cohort study examined the hazard of hip fractures in 1844 male former athletes and 1216 population controls and in relation to exercise volume and intensity in later years. Incident hip fractures after age 50 years were identified from hospital discharge register from 1972 to 2015. Exercise and covariate information was obtained from questionnaires administered in 1985, 1995, 2001, and 2008. Analyses were conducted using extended proportional hazards regression model for time-dependent exposures and effects. During the mean +/- SD follow-up of 21.6 +/- 10.3 years, 62 (3.4%) athletes and 38 (3.1%) controls sustained a hip fracture. Adjusted hazard ratio (HR) indicated no statistically significant difference between athletes and controls (0.84; 95% confidence interval [CI], 0.55-1.29). In subgroup analyses, adjusted HRs for athletes with recent high (>= 15 metabolic equivalent hours [MET-h]/week) and low (= 6 METs at least 75 minutes/week) had initially 77% lower hazard rate (adjusted HR 0.23; 95% CI, 0.06-0.86) than controls. However, the HR was time-dependent (adjusted HR 1.04; 95% CI, 1.01-1.07); by age 75 years the HRs for the athletes with vigorous-intensity exercise reached the level of the controls, but after 85 years the HRs for these athletes increased approximately 1.3-fold annually relative to the controls. In conclusion, these data suggest that continuation of vigorous-intensity exercise is associated with lower HR of hip fracture up to old age. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
  • Valkama, Saara; Holmlund-Suila, Elisa; Ireland, Alex; Hauta-alus, Helena; Enlund-Cerullo, Maria; Rosendahl, Jenni; Andersson, Sture; Mäkitie, Outi (2020)
    Background: Peripheral quantitative computed tomography (pQCT) is a useful tool to assess detailed bone characteristics. Its utility in infants is however limited due to lack of reference data and technical challenges. The purpose of this study was to provide data on length- and weight-adjusted pQCT values and to present a quality grading system for healthy children aged 12 and 24 months. Material and methods: As a part of the Vitamin D intervention in Infants (VIDI) trial, we collected pQCT and anthropometric data from 855 children at 12 months and from 784 children at 24 months. Bone mineral content (BMC; mg/mm), volumetric bone mineral density (vBMD; mg/cm(3)), cross-sectional area (CSA; mm(2)), polarmoment of inertia (PMI; mm(4)), and periosteal circumference (PsC; mm) were assessed for total bone at 20% distal site of the left tibia using pQCT (Stratec XCT2000L). We evaluated the impact of scan quality on bone measures. Total bone parameters were assessed for boys and girls separately. The means of the bone parameters were also compared in relation to age. The associations between bone parameters and weight, length, sex and scan quality were analyzed. Results: We included scans with sufficient quality (Grade 1-5) in the final analyses: 679/855 (79%) at 12 months and 709/784 (90%) at 24 months. Altogether 39% of the scans at 12 months and 51% at 24 months were of good or excellent quality (Grade 1-2). Scan quality had an impact on BMCs at 12 and 24 months (p = 0.001 and p = 0.017, respectively) but not on other bone parameters. Boys presented greater total bone BMC, CSA, PMI and PsC values at 12 and 24 months but vBMDs were similar. All bone parameters showed a significant increase between 12 and 24 months for both sexes. When adjusting bone parameters for weight, length and scan quality, differences between sexes disappeared. Weight was the strongest modifier of BMC, CSA, PMI and PsS at 12 and 24 months. Conclusions: This study increases our understanding on bone parameters in young children and demonstrates the suitability of pQCT in bone research in infants. The described pQCT data and scan quality grading system should prove useful in evaluating data reliability in research settings. Clinical trial registration number: NCT1723852
  • Costantini, Alice; Skarp, Sini; Kampe, Anders; Mäkitie, Riikka E.; Pettersson, Maria; Männikkö, Minna; Jiao, Hong; Taylan, Fulya; Lindstrand, Anna; Mäkitie, Outi (2018)
    Early-onset osteoporosis is characterized by low bone mineral density (BMD) and fractures since childhood or young adulthood. Several monogenic forms have been identified but the contributing genes remain inadequately characterized. In search for novel variants and novel candidate loci, we screened a cohort of 70 young subjects with mild to severe skeletal fragility for rare copy-number variants (CNVs). Our study cohort included 15 subjects with primary osteoporosis before age 30 years and 55 subjects with a pathological fracture history and low or normal BMD before age 16 years. A custom-made high-resolution comparative genomic hybridization array with enriched probe density in >1,150 genes important for bone metabolism and ciliary function was used to search for CNVs. We identified altogether 14 rare CNVs. Seven intronic aberrations were classified as likely benign. Five CNVs of unknown clinical significance affected coding regions of genes not previously associated with skeletal fragility (ETV1-DGKB, AGBL2, ATM, RPS6KL1-PGF, and SCN4A). Finally, two CNVs were pathogenic and likely pathogenic, respectively: a 4 kb deletion involving exons 1-4 of COL1A2 (NM_000089.3) and a 12.5 kb duplication of exon 3 in PLS3 (NM_005032.6). Although both genes have been linked to monogenic forms of osteoporosis, COL1A2 deletions are rare and PLS3 duplications have not been described previously. Both CNVs were identified in subjects with significant osteoporosis and segregated with osteoporosis within the families. Our study expands the number of pathogenic CNVs in monogenic skeletal fragility and shows the validity of targeted CNV screening to potentially pinpoint novel candidate loci in early-onset osteoporosis.
  • Nurmi-Lüthje, I.; Tiihonen, R.; Paattiniemi, E. -L.; Naboulsi, H.; Pigg, S.; Sarkkinen, H.; Kaukonen, J-P; Toivanen, A.; Salmio, K.; Kataja, M.; Lüthje, P. (2018)
    Hypovitaminosis D is a problem among hip fracture patients. In a 1-year cohort study comprising 245 hip fracture patients (mean age of females 81 years and males 78 years) from south-eastern Finland, the mean 25-hydroxyvitamin D [S-25(OH)D] concentration was 73(SD 31) nmol/L. Vitamin D supplementation has been integrated into our current practice. The objectives of this study are to verify vitamin D levels among hip fracture patients and to compare the results with a similar study conducted in the same two hospitals covering the same geographic area 12 years ago. A prospective cohort comprising 245 Caucasian hip fracture patients was enrolled in the study in two acute hospitals in south-eastern Finland (61A degrees N) over a 12-month period in 2015-2016. The S-25(OH)D was measured using 25-hydroxyvitamin D electrochemiluminescence binding assay. The S-25(OH)D concentrations were compared with the corresponding concentrations of a similar cohort analyzed in the same two hospitals 12 years ago. Of the 245 patients, 70% were women with a mean age of 81 (SD 10) years, while the men had a mean age of 78 (SD 12) years (p <0.01). The total mean S-25(OH)D concentration was 73 (SD 31.3) nmol/L. Regional differences were found: 15% in hospital A and 36% in hospital B had a S-25(OH(D level <50 nmol/L, and the mean S-25(OH)D level was 79.2 (SD 31.7) nmol/L in hospital A and 62.4 (SD 27.5) nmol/L in hospital B (p <0.001). No differences were found in S-25(OH)D concentrations by either the place of residence or the time of year. Overall, the percentage of patients with a sufficient vitamin D level (> 50 nmol/L) was remarkably higher in 2015-2016 (77%) than in 2003-2004 (22%). Our results indicate that vitamin D supplementation has been widely integrated into our current practice. However, regional differences were found in the S-25(OH)D concentrations for which the reasons are unknown.
  • Puolakkainen, Tero; Rummukainen, Petri; Lehto, Jemina; Ritvos, Olli; Hiltunen, Ari; Saamanen, Anna-Marja; Kiviranta, Riku (2017)
    Fractures still present a significant burden to patients due to pain and periods of unproductivity. Numerous growth factors have been identified to regulate bone remodeling. However, to date, only the bone morphogenetic proteins (BMPs) are used to enhance fracture healing in clinical settings. Activins are pleiotropic growth factors belonging to the TGF-beta superfamily. We and others have recently shown that treatment with recombinant fusion proteins of activin receptors greatly increases bone mass in different animal models by trapping activins and other ligands thus inhibiting their signaling pathways. However, their effects on fracture healing are less known. Twelve-week old male C57Bl mice were subjected to a standardized, closed tibial fracture model. Animals were divided into control and treatment groups and were administered either PBS control or a soluble activin type IIB receptor (ActRIIB-Fc) intraperitoneally once a week for a duration of two or four weeks. There were no significant differences between the groups at two weeks but we observed a significant increase in callus mineralization in ActRIIB-Fc-treated animals by microcomputed tomography imaging at four weeks. Bone volume per tissue volume was 60%, trabecular number 55% and bone mineral density 60% higher in the 4-week calluses of the ActRIIB-Fc-treated mice (p<0.05 in all). Biomechanical strength of 4-week calluses was also significantly improved by ActRIIBFc treatment as stiffness increased by 64% and maximum force by 45% (p<0.05) compared to the PBS-injected controls. These results demonstrate that ActRIIB-Fc treatment significantly improves healing of closed long bone fractures. Our findings support the previous reports of activin receptors increasing bone mass but also demonstrate a novel approach for using ActRIIB-Fc to enhance fracture healing.
  • Helin-Salmivaara, Arja; Korhonen, Maarit J.; Lehenkari, Petri; Junnila, Seppo Y. T.; Neuvonen, Pertti J.; Ruokoniemi, Päivi; Huupponen, Risto (2012)
  • Koromani, Fjorda; Alonso, Nerea; Alves, Ines; Brandi, Maria Luisa; Foessl, Ines; Formosa, Melissa M.; Morgenstern, Milana Frenkel; Karasik, David; Kolev, Mikhail; Makitie, Outi; Ntzani, Evangelia; Obermayer-Pietsch, Barbara; Ohlsson, Claes; Rauner, Martina; Soe, Kent; Soldatovic, Ivan; Teti, Anna; Valjevac, Amina; Rivadeneira, Fernando (2021)
    Musculoskeletal research has been enriched in the past ten years with a great wealth of new discoveries arising from genome wide association studies (GWAS). In addition to the novel factors identified by GWAS, the advent of whole-genome and whole-exome sequencing efforts in family based studies has also identified new genes and pathways. However, the function and the mechanisms by which such genes influence clinical traits remain largely unknown. There is imperative need to bring multidisciplinary expertise together that will allow translating these genomic discoveries into useful clinical applications with the potential of improving patient care. Therefore "GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork" (GEMSTONE) aims to set the ground for the: 1) functional characterization of discovered genes and pathways; 2) understanding of the correspondence between molecular and clinical assessments; and 3) implementation of novel methodological approaches. This research network is funded by The European Cooperation in Science and Technology (COST). GEMSTONE includes six working groups (WG), each with specific objectives: WG1-Study populations and expertise groups: creating, maintaining and updating an inventory of experts and resources (studies and datasets) participating in the network, helping to assemble focus groups defined by phenotype, functional and methodological expertise. WG2-Phenotyping: describe ways to decompose the phenotypes of the different functional studies into meaningful components that will aid the interpretation of identified biological pathways. WG3 Monogenic conditions - human KO models: makes an inventory of genes underlying musculoskeletal monogenic conditions that aids the assignment of genes to GWAS signals and prioritizing GWAS genes as candidates responsible for monogenic presentations, through biological plausibility. WG4 Functional investigations: creating a roadmap of genes and pathways to be prioritized for functional assessment in cell and organism models of the musculoskeletal system. WG5 Bioinformatics seeks the integration of the knowledge derived from the distinct efforts, with particular emphasis on systems biology and artificial intelligence applications. Finally, WG6 Translational outreach: makes a synopsis of the knowledge derived from the distinct efforts, allowing to prioritize factors within biological pathways, use refined disease trait definitions and/or improve study design of future investigations in a potential therapeutic context (e.g. clinical trials) for musculoskeletal diseases.
  • Mäkitaipale, Johanna; Sievänen, Harri; Laitinen-Vapaavuori, Outi (2018)
    Rabbit bones are brittle and prone to fissure formation. Radiographs of very young and old rabbits are often indicative of decreased bone density. The aim of this study was to investigate the tibial bone parameters in pet rabbits, and their association with age, sex, castration and dental disease. Eighty-seven (43 female/5 spayed, 44 male/19 castrated) pet rabbits (mean age 2.6 years, range 0.3-9.3 years) of various breeds were studied, of which 37 had dental disease. Right tibiae were scanned with peripheral quantitative CT at the distal (4percent) and mid-shaft sites (50percent of the tibial length). Analysed bone parameters included the total cross-sectional area, cortical bone area and density, trabecular bone density and strength-strain index. The mean diaphyseal cortical density was high (about 1400 mg/cm(3)) in comparison to many other species. Within the studied age range, age was weakly but positively associated with diaphyseal cortical density, with the juvenile rabbits clearly showing the lowest values. There was no tendency for age-related decrease in trabecular or cortical bone density at least up to six years of age. Neither were sex, castration nor dental disease associated with decreased tibial bone density.