Critical points in strategies for the diagnosis and treatment of osteoporosis

Current treatment decisions for osteoporosis depend on the fracture risk calculated based on the results of comprehensive diagnostic procedures [clinical risk factors (CRF), densitometry (BMD), morphometry, and bone turnover markers (BTM)]. Recently developed fracture risk assessment tool (FRAXTM) represents an important new achievement as a 10-year fracture risk calculation based on femoral neck densitometry and age combined with independent clinical fracture risk factors. FRAXTM presents several options: FRAXTM BMI (body mass index) is advocated as a helpful screening tool to identify the group of patients with high fracture risk, independently of access to densitometry and FRAXTM, utilizing hip densitometry. In both cases, the probability of major fractures or hip fractures are calculated during performed diagnostic evaluations. Operating FRAXTM algorithm does not include spinal bone mineral density, which is its main limitation. With the aim of improvement of anti-fracture efficacy of therapeutic management of osteoporosis, we have extended our discussion to three integral elements of existent strategy: 1) screening outlines, 2) principles of drug selection, and 3) treatment benefit evaluation. Since osteoporosis is a chronic disease, long-term adherence to the treatment is important. The suitability of the drug, the patient’s preference, tolerability, and convenience should all be considered. Anti-catabolic drugs are most appropriate in patients with high bone turnover, while anabolic drugs demonstrate efficacy irrespective of bone turnover. BMD measurement is most widely used for long-term assessment of the efficacy of osteoporosis treatment. The measurements of bone turnover markers (BTMs) can be considered a useful shortterm (at 3 months) monitoring tool in selected patients. In both BTM and BMD, the least significant change (LSC) method should be used for interpretation of the results. Fractures are not a reliable clinical endpoint for evaluating the effectiveness of therapy in individual patients because of their stochastic nature. If fractures occur, however, the need for drug change and additional non-pharmacological treatment (fall prevention, balance training, muscle strengthening) should always be considered.Kryterium interwencji farmakoterapeutycznej w osteoporozie bez złamań stanowi ocena indywidualnego bezwzględnego 10-letniego ryzyka złamań, określonego na podstawie kompleksowej analizy czynników ryzyka złamań. Kompleksowa ocena ryzyka złamań w perspektywie 10-letniej integruje wyniki badań diagnostycznych (densytometria, ocena bezobjawowych złamań kręgów, ocena metabolizmu kostnego) oraz wybranych klinicznych czynników ryzyka złamań. Wprowadzony w 2008 roku kalkulator FRAXTM (WHO Fracture Risk Assessment Tool) pozwala na szybkie i proste obliczanie 10-letniego ryzyka złamań, które u indywidualnego pacjenta powinno być podstawą do podejmowania dalszych decyzji diagnostycznych i terapeutycznych. FRAXTM opracowany jako kalkulator obliczający 10-letnie ryzyko złamań może być stosowany z uwzględnieniem densytometrii bliższej nasady kości udowej wraz z innymi niezależnymi czynnikami ryzyka złamań. FRAXTM oparty na wskaźniku masy ciała (BMI, body mass index), gęstości mineralnej kości (BMI, bez uwzględnienia pomiaru BMD [bone mineral density]) może być przydatnym narzędziem przesiewowym dla lekarzy pierwszego kontaktu oceniających ryzyko złamań (case finding strategy), zwłaszcza w przypadku ograniczonego dostępu do densytometrii. W obu przypadkach FRAXTM może oceniać 10-letnie ryzyko złamania bliższej nasady kości udowej oraz wszystkich złamań osteoporotycznych. Głównym ograniczeniem algorytmu FRAXTM jest brak możliwości wykorzystania wyników badań densytometrycznych w lokalizacji kręgosłupa lędźwiowego. O ile decyzja, co do potrzeby leczenia farmakologicznego osteoporozy opiera się głównie na wielkości przewidywanego 10-letniego ryzyka złamania, to zasadniczymi kryteriami wyboru leku u indywidualnego pacjenta powinny być skuteczność przeciwzłamaniowa leku, oceniana w randomizowanych, kontrolowanych badaniach klinicznych, oraz potencjalne działania niepożądane, dostępność i łatwość stosowania. Na wybór leku wpływa także mechanizm jego działania: leki przeciwresorpcyjne są najbardziej skuteczne u chorych z zaawansowanym zanikiem kostnym i szybkim obrotem metabolicznym kości, podczas gdy leki anaboliczne lub podwójnym punkcie uchwytu (ranelinian strontu) działają niezależnie od wyjściowych wartości BMD czy aktywności obrotu kostnego. "Złotym standardem" leczenia osteoporozy pozostają bisfosfoniany. Ocena efektywności prowadzonej farmakoterapii jest jednym z ważniejszych elementów strategii w postępowaniu przeciwzłamaniowym. Pomiar BMD jest uznanym długoterminowym wskaźnikiem zastępczym oceny wytrzymałości mechanicznej kości. Wskaźnikiem krótkoterminowym oceny efektywności terapii (3 miesiące) jest pomiar poziomu markerów obrotu kostnego w surowicy. W obu przypadkach podstawowym kryterium interpretacyjnym powinna być najmniejsza znacząca zmiana (LSC, least significant change). Interpretacja znaczenia złamania kości w trakcie terapii antyzłamaniowej jest niejednoznaczna. Złamań nie należy interpretować jako bezwzględnego wskaźnika braku efektywności stosowanej farmakoterapii, należy jednak ponownie zanalizować dane pacjenta, wprowadzając zwłaszcza modyfikację postępowania niefarmakologicznego

Mechanizmy działania leków antykatabolicznych stosowanych w osteoporozie

Bone remodeling is essential for skeletal and the whole body health. Imbalance in skeletal turnover, so that bone resorption exceeds bone formation, may lead to reduction in bone strength and increase fractures risk. The main target of anticatabolic therapy is to normalize increased osteoclasts activity and bone turnover. Molecular mechanisms of action of this class of drugs are related with different points in cellular signaling pathways that control osteoclasts differentiation and resorbing activity. These mechanisms are briefly described in our review.Procesy przebudowy tkanki kostnej leżą u podstawy prawidłowego funkcjonowania układu szkieletowego i całego organizmu. Zachwianie równowagi pomiędzy procesami kościotworzenia a resorpcją, na korzyść resorpcji kostnej, może prowadzić do obniżenia wytrzymałości mechanicznej kości i do złamań. Głównym celem działania leków antykatabolicznych jest normalizacja nadmiernej aktywności resorpcyjnej osteoklasta i podwyższonego obrotu kostnego. Molekularne mechanizmy działania leków z tej grupy wykorzystują różne punkty w sygnalizacji zewnątrz- i wewnątrzkomórkowej prowadzącej do różnicowania bądź aktywności resorpcyjnej osteoklastów. W niniejszej pracy krótko je opisano

Jakość badań densytometrycznych w Polsce : wyniki oceny wstępnej

Background: The quality of measurements is the main problem in clinical diagnostics. Only a well-designed and properly implemented quality control system ensures that real and precise measurement results are obtained. The aim of our study was to evaluate the quality of bone mineral density measurements in laboratories in Poland. Material/Methods: 15 laboratories from 9 cities participated in the study. The evaluation was performed on the basis of International Society for Clinical Densitometry recommendations and data from the literature. Part I of the evaluation comprised checking the calibration and stability of the densitometer, the safety of acquisition data, the documentation of services, and the reproducibility of measurements in patients. Part II comprised reproducibility, based on phantom testing, using European spine phantom and anthropomorphic spine phantom. Phantom measurements and analysis were done in a routine manner by native operators. Results: The only activity which was properly and regularly performed in all laboratories was calibration. The other activities were performed properly in less than half of the laboratories, and some of them only in single laboratories. In nearly half of the laboratories the reproducibility error exceeded the tolerance limit. Conclusions: The present study suggests that the quality of bone mineral density measurement in Poland is rather low. Introducing quality control in laboratories and training courses for operators is strongly recommended

Guidelines for the diagnosis and management of osteoporosis in Poland. Update 2022

Guidelines to provide an update of the previously published Polish recommendations for the management of women and men with osteoporosis have been developed in line with advances in medical knowledge, evidence-based data, and new concepts in diagnostic and therapeutic strategies. A Working Group of experts from the Multidisciplinary Osteoporosis Forum and from the National Institute of Geriatrics, Rheumatology, and Rehabilitation in Warsaw performed a thorough comprehensive review of current relevant publications in the field (including all age groups of people and management of secondary osteoporosis), and they evaluated epidemiological data on osteoporosis in Poland and the existing standards of care and costs. A voting panel of all co-authors assessed and discussed the quality of evidence to formulate 29 specific recommendations and voted independently the strength of each recommendation. This updated practice guidance highlights a new algorithm of the diagnostic and therapeutic procedures for individuals at high and very high fracture risk and presents a spectrum of general management and the use of medication including anabolic therapy. Furthermore, the paper discusses the strategy of primary and secondary fracture prevention, detection of fragility fractures in the population, and points to vital elements for improving management of osteoporosis in Poland

Management of osteoporosis in central and eastern Europe (CEE): conclusions of the “2nd Summit on Osteoporosis—CEE”, 21–22 November 2008, Warsaw, Poland

In November 2008, the “2nd Summit on Osteoporosis—Central and Eastern Europe (CEE)” was held in Warsaw, Poland. Discussions at this meeting focused on the identification and discussion of diagnostic, preventive, and therapeutic measures used in CEE. Evaluated information was used to identify issues regarding diagnosis and therapy of osteoporosis in these countries to facilitate the subsequent setup of appropriate support and development strategies. The main debate was structured according to the following five subjects: (1) present status and future perspectives for implementation of FRAX® into local (CEE) diagnostic algorithms, (2) principles of drug selection in osteoporosis treatment in CEE countries, (3) nonpharmacological interventions in osteoporosis treatment and prophylaxis in CEE countries, (4) treatment benefit evaluation, and (5) cost–effectiveness and evaluation of reimbursement policies in CEE countries. The most important and substantial comments of the delegates are summarized in the present article. The multinational panel of experts with representatives from many CEE countries as well as Austria and Switzerland made the “2nd Summit on Osteoporosis—CEE” a perfect platform to identify issues and needs regarding diagnosis and therapy of osteoporosis as well as the cost–effectiveness of osteoporosis management in CEE countries. The information gained will serve as a basis for the development of strategies to resolve the identified issues at the “3rd Summit on Osteoporosis—CEE” in November 2009

Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe — recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency

Wstęp: Wyniki badań z ostatnich lat dokumentują wiele korzyści wynikających z działania witaminy D na organizm człowieka na wszystkichetapach jego życia. Większość badań epidemiologicznych sugeruje, że niedobór witaminy D jest powszechny wśród mieszkańców EuropyŚrodkowej. Naturalną konsekwencją tej sytuacji jest konieczność ciągłego uświadamiania społeczeństwu oraz środowisku medycznemu,jaką rolę odgrywa witamina D w rozwoju i funkcjonowaniu organizmu ludzkiego.Metody: Na podstawie przeglądu danych literaturowych Polski Zespół Wielodyscyplinarny opracował tezy dotyczące zasad suplementacjiwitaminą D, które przesłano do członków Komitetu Naukowego konferencji „Witamina D — minimum, maksimum, optimum”,19–20 Październik, 2012, Warszawa. W trakcie powyższej konferencji z udziałem 550 delegatów oraz Ekspertów różnych dziedzin medycynyomówiono i przedyskutowano propozycje wytycznych suplementacji witaminą D populacji Europy Środkowej.Wyniki: W efekcie przeprowadzonych dyskusji Zespół Ekspertów opracował wytyczne suplementacji witaminą D dla wszystkich grupwiekowych populacji Europy Środkowej. Określono również kryteria diagnostyczne charakteryzujące stan zaopatrzenia organizmu w witaminę D: deficyt witaminy D ustalono jako stężenie 25(OH)D < 20 ng/mL (< 50 nmol/L)], suboptymalne zaopatrzenie jako stężenie25(OH)D wynoszące 20–30 ng/mL (50–75 nmol/L), a stężenie 30–50 ng/mL (75–125 nmol/L) uznano za docelowe dla zapewnienia efektuplejotropowego witaminy D.Wnioski: Poprawa obecnego stanu zaopatrzenia witaminy D w grupach dzieci, młodzieży, osób aktywnych zawodowo i seniorówpowinna zostać włączona do priorytetów polityki zdrowotnej społeczeństw Europy Środkowej.Introduction: Adequate Vitamin D intake and its concentration in serum are important for bone health and calcium–phosphate metabolismas well as for optimal function of many organs and tissues. Documented trends in lifestyle, nutritional habits and physical activityappear to be associated with moderate or severe Vitamin D deficits resulting in health problems. Most epidemiological studies suggest thatVitamin D deficiency is prevalent among Central European populations. Concern about this problem led to the organising of a conferencefocused on overcoming Vitamin D deficiency.Methods: After reviewing the epidemiological evidence and relevant literature, a Polish multidisciplinary group formulated theses onrecommendations for Vitamin D screening and supplementation in the general population. These theses were subsequently sent to ScientificCommittee members of the ‘Vitamin D — minimum, maximum, optimum’ conference for evaluation based on a ten-point scale.With 550 international attendees, the meeting ‘Vitamin D — minimum, maximum, optimum’ was held on October 19–20, 2012 in Warsaw(Poland). Most recent scientific evidence of both skeletal and non-skeletal effects of Vitamin D as well as the results of panellists’ votingwere reviewed and discussed during eight plenary sessions and two workshops.Results: Based on many polemical discussions, including post-conference networking, the key opinion leaders established ranges ofserum 25-hydroxyVitamin D concentration indicating Vitamin D deficiency [< 20 ng/mL (< 50 nmol/L)], suboptimal status [20–30 ng/mL(50–75 nmol/L)], and target concentration for optimal Vitamin D effects [30–50 ng/mL (75–125 nmol/L)]. General practical guidelines regardingsupplementation and updated recommendations for prophylactic Vitamin D intakes in Central European neonates, infants, childrenand adolescents as well as in adults (including recommendations for pregnant and breastfeeding women and the elderly) were developed.Conclusions: Improving the Vitamin D status of children, adolescents, adults and the elderly must be included in the priorities of physicians,healthcare professionals and healthcare regulating bodies. The present paper offers elaborated consensus on supplementationguidance and population strategies for Vitamin D in Central Europe

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms