Eesti traumatoloogide-ortopeedide selts 40

Eesti Arst 2016; 95(11):74

Rasedusest tingitud luude hõrenemine tervel

Raseduse ajal kujunenud muutused luukoes – luude tiheduse vähenemine – on pöörduva iseloomuga ja taanduvad hiljem täielikult. Artiklis on kirjeldatud 35aastase naise haigusjuhtu. Patsiendil tehti luutiheduse uuringud enne rasedust ning kahe kuu, ühe ja kahe aasta möödumisel sünnitusest. Vahetult pärast sünnitust registreeritud reieluu ja nimmelülide luutiheduse vähenemine paranes aasta möödudes täielikult. Tegemist oli terve naisega, kel rasedus ja sünnitus kulgesid normaalselt. Eesti Arst 2007; 86(8):521-52

Luude kvaliteedi sõeluuringud kvantitatiivse ultraheli meetodil

Ultraheli kasutamise eelisteks luukoe hindamise sõeluuringutes peetakse kiirguse puudumist, odavust, läbiviimise lihtsust ja kiirust, kuid enim kasutatav luude tiheduse määramise meetod on siiski DXA (kaheenergialine röntgenabsorptsiomeetria). Luude kvaliteedi hindamise uuringu eesmärgiks oli võrrelda 1998. a tervete naiste uurimisel saadud andmeid tervisekontrolli andmetega. Luude seisundit uuriti kokku ligi 7000 naisel Eesti eri piirkondades. Andmete võrdlemisel selgus, et vanemates vanuserühmades oli tervisepäevadel osalenud naistel osteoporoosi esinemissagedus oluliselt väiksem kui tervete naiste hulgas 1998. a. Igas järgnevas vanuserühmas osteoporoosi esinemissagedus suurenes. Kuna valimid ei olnud otseselt võrreldavad, ei saa siiski teha järeldust, nagu oleks Eestis naiste luude kvaliteet oluliselt paranenud. Eesti Arst 2009; 88(Lisa3):52−5

Mutational analysis of COL1A1 and COL1A2 genes among Estonian osteogenesis imperfecta patients

Background Osteogenesis imperfecta (OI) is a rare bone disorder. In 90% of cases, OI is caused by mutations in the COL1A1/2 genes, which code procollagen α1 and α2 chains. The main aim of the current research was to identify the mutational spectrum of COL1A1/2 genes in Estonian patients. The small population size of Estonia provides a unique chance to explore the collagen I mutational profile of 100% of OI families in the country. Methods We performed mutational analysis of peripheral blood gDNA of 30 unrelated Estonian OI patients using Sanger sequencing of COL1A1 and COL1A2 genes, including all intron-exon junctions and 5′UTR and 3′UTR regions, to identify causative OI mutations. Results We identified COL1A1/2 mutations in 86.67% of patients (26/30). 76.92% of discovered mutations were located in the COL1A1 (n = 20) and 23.08% in the COL1A2 (n = 6) gene. Half of the COL1A1/2 mutations appeared to be novel. The percentage of quantitative COL1A1/2 mutations was 69.23%. Glycine substitution with serine was the most prevalent among missense mutations. All qualitative mutations were situated in the chain domain of pro-α1/2 chains. Conclusion Our study shows that among the Estonian OI population, the range of collagen I mutations is quite high, which agrees with other described OI cohorts of Northern Europe. The Estonian OI cohort differs due to the high number of quantitative variants and simple missense variants, which are mostly Gly to Ser substitutions and do not extend the chain domain of COL1A1/2 products

RNA sequencing analysis reveals increased expression of interferon signaling genes and dysregulation of bone metabolism affecting pathways in the whole blood of patients with osteogenesis imperfecta

Background Osteogenesis imperfecta (OI) is a rare genetic disorder in which the patients suffer from numerous fractures, skeletal deformities and bluish sclera. The disorder ranges from a mild form to severe and lethal cases. The main objective of this pilot study was to compare the blood transcriptional landscape of OI patients with COL1A1 pathogenic variants and their healthy relatives, in order to find out different gene expression and dysregulated molecular pathways in OI. Methods We performed RNA sequencing analysis of whole blood in seven individuals affected with different OI severity and their five unaffected relatives from the three families. The data was analyzed using edgeR package of R Bioconductor. Functional profiling and pathway analysis of the identified differently expressed genes was performed with g:GOSt and MinePath web-based tools. Results We identified 114 differently expressed genes. The expression of 79 genes was up-regulated, while 35 genes were down-regulated. The functional analysis identified a presence of dysregulated interferon signaling pathways (IFI27, IFITM3, RSAD12, GBP7). Additionally, the expressions of the genes related to extracellular matrix organization, Wnt signaling, vitamin D metabolism and MAPK-ERK 1/2 pathways were also altered. Conclusions The current pilot study successfully captured the differential expression of inflammation and bone metabolism pathways in OI patients. This work can contribute to future research of transcriptional bloodomics in OI. Transcriptional bloodomics has a strong potential to become a major contributor to the understanding of OI pathological mechanisms, the discovery of phenotype modifying factors, and the identification of new therapeutic targets. However, further studies in bigger cohorts of OI patients are needed to confirm the findings of the current work

Transcriptional landscape analysis identifies differently expressed genes involved in follicle-stimulating hormone induced postmenopausal osteoporosis

Osteoporosis is a disorder associated with bone tissue reorganization, bone mass, and mineral density. Osteoporosis can severely affect postmenopausal women, causing bone fragility and osteoporotic fractures. The aim of the current study was to compare blood mRNA profiles of postmenopausal women with and without osteoporosis, with the aim of finding different gene expressions and thus targets for future osteoporosis biomarker studies. Our study consisted of transcriptome analysis of whole blood serum from 12 elderly female osteoporotic patients and 12 non-osteoporotic elderly female controls. The transcriptome analysis was performed with RNA sequencing technology. For data analysis, the edgeR package of R Bioconductor was used. Two hundred and fourteen genes were expressed differently in osteoporotic compared with non-osteoporotic patients. Statistical analysis revealed 20 differently expressed genes with a false discovery rate of less than 1.47 × 10(−4) among osteoporotic patients. The expression of 10 genes were up-regulated and 10 down-regulated. Further statistical analysis identified a potential osteoporosis mRNA biomarker pattern consisting of six genes: CACNA1G, ALG13, SBK1, GGT7, MBNL3, and RIOK3. Functional ingenuity pathway analysis identified the strongest candidate genes with regard to potential involvement in a follicle-stimulating hormone activated network of increased osteoclast activity and hypogonadal bone loss. The differentially expressed genes identified in this study may contribute to future research of postmenopausal osteoporosis blood biomarkers

Alternative splicing of leptin receptor overlapping transcript in osteosarcoma

Alternative splicing of RNA is an essential mechanism that increases proteomic diversity in eukaryotic cells. Aberrant alternative splicing is often associated with various human diseases, including cancer. We conducted whole-transcriptome analysis of 18 osteosarcoma bone samples (paired normal—tumor biopsies). Using RNA-seq, we identified statistically significant (FDR <0.05) 26 differentially expressed transcript variants of leptin receptor overlapping transcript (LEPROT) gene. Some of the transcripts were overexpressed in normal cells, whereas others were overexpressed in tumor cells. The function of LEPROT is not completely understood. Herein, we highlight a possible association between OS and aberrant alternative splicing events and its interaction with the expression of LEPROT. We also discuss the role of LEPROT in regulating growth hormone and its receptor, and the relationship with initiation and progression of OS. This research study may help to understand the association of alternative splicing mechanism in OS and in tumorigenesis more generally. Further, LEPROT gene can also be considered as a potential biomarker of osteosarcoma

Trends in and relation between hip fracture incidence and osteoporosis medication utilization and prices in Estonia in 2004-2015

Summary Osteoporosis medicines reduce osteoporotic fractures. There is a very strong negative correlation between the consumption of medicines and the price of an average daily dose indicating that affordability is a key factor that could increase consumption of antiosteoporotic medicines and, through that, reduce fractures. Purpose Osteoporosis is a major cause of morbidity and mortality in the modern world. Our study aims to describe the trends in incidence of hip fractures in relation to drug utilization patterns and the average price of antiosteoporotic medicines in Estonia. Methods Data on hip fractures was obtained from the medical claims database of Estonian Health Insurance Fund (EHIF). Consumption and price data was obtained from the Estonian State Agency of Medicines (SAM).Consumption is presented using WHO defined daily doses methodology, and the prices reflect the average wholesale price of medicines. Results From 2004 to 2010 there was a non-significant increasing trend in standardized hip fracture incidence in Estonia, but from 2010 to 2015, the trend turned to a significant decrease of 4.5% per year. The consumption of osteoporosis medication increased significantly from 2004 to 2009 by yearly average of 41.2%. After 2009, the consumption levelled. On contrast, the average price of one daily dose of osteoporosis medication decreased significantly from 2004 to 2009 by 16.9% per year and the decrease also levelled after 2009. This gives a very strong negative correlation of −0.93 (p < 0.001) between the consumption of antiosteoporotic medication and the average price of a daily dose of medication during the study period. Conclusions The statistically significant decline of standardized incidence of hip fractures from 2010 onward could at least in part be the result of the high increase in consumption of antiosteoporotic medicines which in turn is strongly negatively correlated with the average price of osteoporosis medicines

Adherence to osteoporosis medicines in Estonia-a comprehensive 15-year retrospective prescriptions database study

Summary Some patients do not take medicines as they are supposed to. Our research showed that in Estonia, one fifth of patients did not start treatment with osteoporosis medicines and only 20% used the medicines for at least 3 years as they should. This induces unnecessary costs to the healthcare system. Purpose Medication non-adherence is the number one reason for not obtaining the expected clinical effect of medicines. With osteoporosis treatment, it has been shown that both implementation of treatment and persistence influence the risk of fractures significantly. Long-term adherence to medication in Estonia is to be determined with this study. Methods A 15-year retrospective study was carried out in order to establish initiation, implementation, and persistence of Estonian patients. All new users of osteoporosis medicines were analyzed for all prescriptions they received during the study period. Sufficient adherence to treatment was defined as a patient being dispensed 80% or more prescribed doses for at least 1 year. Results The study period was from 2001 to 2015. Patients (24,652) were included in the study. Of the patients, 93.7% (n = 23,091) were women and 6.3% (n = 1564) were men. Eighteen percent (4636) were dispensed only one prescription. Of the patients, 44.2% included in the study had medication possession ratio (MPR) ≥80% over follow-up period; 8922 (36.2%) who were prescribed from 2001 to 2015 persisted for 1 year with MPR ≥80% and 19.8% persisted for 3 years. Forty percent of expenditure on osteoporosis medication was made for treatment courses with insufficient adherence. Conclusions There is room for improvement in Estonia with medication adherence relating to all three aspects that determine adherence—initiation, implementation, and persistence. This means further efforts are to be made to educate patients and healthcare professionals on realizing the importance of good adherence

Mutation analysis of the <i>COL1A1</i> and <i>COL1A2</i> genes in Vietnamese patients with osteogenesis imperfecta

BackgroundThe genetics of osteogenesis imperfecta (OI) have not been studied in a Vietnamese population before. We performed mutational analysis of the COL1A1 and COL1A2 genes in 91 unrelated OI patients of Vietnamese origin. We then systematically characterized the mutation profiles of these two genes which are most commonly related to OI.MethodsGenomic DNA was extracted from EDTA-preserved blood according to standard high-salt extraction methods. Sequence analysis and pathogenic variant identification was performed with Mutation Surveyor DNA variant analysis software. Prediction of the pathogenicity of mutations was conducted using Alamut Visual software. The presence of variants was checked against Dalgleish's osteogenesis imperfecta mutation database.ResultsThe sample consisted of 91 unrelated osteogenesis imperfecta patients. We identified 54 patients with COL1A1/2 pathogenic variants; 33 with COL1A1 and 21 with COL1A2. Two patients had multiple pathogenic variants. Seventeen novel COL1A1 and 10 novel COL1A2 variants were identified. The majority of identified COL1A1/2 pathogenic variants occurred in a glycine substitution (36/56, 64.3 %), usually serine (23/36, 63.9 %). We found two pathogenic variants of the COL1A1 gene c.2461G > A (p.Gly821Ser) in four unrelated patients and one, c.2005G > A (p.Ala669Thr), in two unrelated patients.ConclusionOur data showed a lower number of collagen OI pathogenic variants in Vietnamese patients compared to reported rates for Asian populations. The OI mutational profile of the Vietnamese population is unique and related to the presence of a high number of recessive mutations in non-collagenous OI genes. Further analysis of OI patients negative for collagen mutations, is required