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ZusammenfassungDie X-chromosomale Hypophosphatämie (XLH, OMIM 307800) ist eine seltene Knochenerkrankung, die durch Mutationen in PHEX (PHEX phosphate regulating endopeptidase X-linked) verursacht wird. Rachitis, Osteomalazie, Kleinwuchs und komplexe Beindeformitäten gehören zu den wichtigsten skelettalen Veränderungen dieser Erkrankung. Die konservative Therapie mit Phosphatsalzen oder FGF23-hemmenden Antikörpern kann Beschwerden nachweislich verbessern. Dennoch zeigen rezente Studien eindrücklich das Ausmaß der Krankheitstypischen Gangveränderungen, Beindeformitäten und damit einhergehenden Verminderung der Lebensqualität. Ein bedeutendes orthopädisches Behandlungsziel an der unteren Extremität ist der Erhalt bzw. die Herstellung physiologischer Beinachsenstellung. Dieser Artikel fasst die orthopädische Therapie von Beindeformitäten bei Kindern und Erwachsenen mit XLH in einem multidisziplinären Setting zusammen.

Context MicroRNAs (miRNAs)—short, single-stranded, noncoding RNAs—regulate several biological processes, including bone metabolism. Objective We investigated circulating miRNAs as promising biomarkers for treatment monitoring in women with postmenopausal osteoporosis on denosumab (DMAB) therapy. Methods In this prospective, observational, single-center study, 21 postmenopausal women treated with DMAB were included for a longitudinal follow-up of 2 years. Next-generation sequencing (NGS) was performed to screen for serological miRNAs at baseline, month 6, and month 24. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to confirm NGS findings in the entire cohort. Bone turnover markers (BTM) P1NP and CTX, and bone mineral density (BMD) by dual x-ray absorptiometry were assessed and correlated to miRNAs. Results BMD at the hip (5.5%, P = 0.0006) and lumbar spine significantly increased (11.4%, P = 0.017), and CTX (64.1%, P < 0.0001) and P1NP (69.3%, P < 0.0001) significantly decreased during treatment. NGS analysis revealed significant changes in miRNAs after 2 years of DMAB treatment but not after 6 months. Seven miRNAs were confirmed by RT-qPCR to be significantly changed during a 2-year course of DMAB treatment compared to baseline. Four of these were mainly transcribed in blood cells, including monocytes. Correlation analysis identified significant correlation between change in miRNA and change in BTMs as well as BMD. Based on effect size and correlation strength, miR-454-3p, miR-26b-5p, and miR-584-5p were defined as top biomarker candidates, with the strongest association to the sustained effect of denosumab on bone in osteoporotic patients. Conclusion Two years of DMAB treatment resulted in upregulation of 7 miRNAs, 4 of which are mainly transcribed in monocytes, indicating a potential impact of DMAB on circulating osteoclast precursor cells. These changes were associated to BMD gain and BTM suppression and could therefore be useful for monitoring DMAB treatment response.

ZusammenfassungDie X‑chromosomale Hypophosphatämie (X-linked hypophosphatemic rickets, XLH, OMIM # 307800) ist eine seltene Erkrankung des Knochenstoffwechsels, die mit einem ausgeprägten Phosphatverlust und oftmals schwerer Beeinträchtigung der Lebensqualität einhergeht. Durch einen bislang noch ungeklärten Pathomechanismus kommt es durch Mutationen in der Endopeptidase PHEX zu einer vermehrten Produktion von Fibroblast Growth Factor 23 (FGF23). Dieser Hauptregulator des Phosphathaushalts verursacht eine pathologisch erhöhte renale Phosphatausscheidung sowie eine Verminderung der Vitamin-D-Aktivierung. Im Kindes- und Jugendalter zählen Rachitis, Wachstumsstörungen sowie mitunter schwere Beindeformitäten zu den Leitsymptomen. Im Erwachsenenalter kommen neben Beinfehlstellungen frühzeitige Gelenksabnutzungen, Weichteilkalzifikationen, Sehnenansatzentzündungen (Enthesitis) sowie Mineralisationsstörungen des Knochens („Pseudofrakturen“), welche die Lebensqualität erheblich beeinträchtigen können, hinzu. Durch das breite Spektrum der Symptome, die bis zu neurochirurgischen Komplikationen wie Syringomyelie und Chiari-Malformationen führen, ist die frühe Diagnose und Anbindung in einem multidisziplinären Setting für die Betreuung der PatientInnen essenziell.Die orale Gabe von Phosphatsalzen und aktiven Vitamin-D-Derivaten stellte bis vor Kurzem die wichtigste pharmakologische Behandlungsoption dar, die vor allem bei frühem Beginn zu einer Abschwächung der Symptomatik führen konnte. Seit der Zulassung von Burosumab, einem Antikörper gegen FGF23, steht für die Behandlung von Kindern und adulten PatientInnen mit XLH eine in den Pathomechanismus eingreifende, therapeutische Option zur Verfügung.

Spondyloarthropathies (SpA) are common systemic inflammatory rheumatic diseases, in which, as in other rheumatic diseases, levels of markers of bone resorption are elevated, leading to bone loss and elevated risk of vertebral fractures. However, the diseases are also associated with new bone formation in the spine, the so-called syndesmophytes. We tried to unravel the pathogenesis of formation and growth of syndesmophytes and evaluated new diagnostic and treatment options. After a successful meeting of the Working Group on Rheumatic Diseases at the ECTS 2020, we (WL and CR) were excited about the quality of the speakers (CM, JH, AG, and GL) and their complimentary lectures. Given the relative lack of reviews on spondyloarthropathies and bone, we decided to work together on a comprehensive review that might be interesting for basic scientists and clinically relevant for clinicians. Radiographic progression in axSpA is linked to several risk factors, like male sex, smoking, HLA-B-27, increased levels of CRP, presence of syndesmophytes, and marked inflammation on MRI. The potential role of mechanical stress in the context of physically demanding jobs has been also suggested to promote structural damages. Different treatment options from NSAIDs to biologic agents like TNF inhibitors (TNFi) or IL-17inhibitors (IL-17i) result in a reduction of inflammation and symptoms. However, all these different treatment options failed to show clear and reproducible results on inhibition on syndesmophyte formation. The majority of data are available on TNFi, and some studies suggested an effect in subgroups of patients with ankylosing spondylitis. Less information is available on NSAIDs and IL-17i. Since IL-17i have been introduced quite recently, more studies are expected. IL-17 inhibitors (Il-17i) potently reduce signs and symptoms, but serum level of IL-17 is not elevated, therefore, IL-17 probably has mainly a local effect. The failure of anti-IL-23 in axSpA suggests that IL-17A production could be independent from IL-23. It may be upregulated by TNFα, resulting in lower expression of DKK1 and RANKL and an increase in osteogenesis. In active AS markers of bone resorption are increased, while bone formation markers can be increased or decreased. Bone Turnover markers and additional markers related to Wnt such as DKK1, sclerostin, and RANKL are valuable for elucidating bone metabolism on a group level and they are not (yet) able to predict individual patient outcomes. The gold standard for detection of structural lesions in clinical practice is the use of conventional radiographics. However, the resolution is low compared to the change over time and the interval for detecting changes are 2 years or more. Modern techniques offer substantial advantages such as the early detection of bone marrow edema with MRI, the fivefold increased detection rate of new or growing syndesmophytes with low-dose CT, and the decrease in 18F-fluoride uptake during treatment with TNFα-inhibitors (TNFi) in a pilot study in 12 AS patients. Detection of bone involvement by new techniques, such as low-dose CT, MRI and 18-Fluoride PET-scans, and bone turnover markers, in combination with focusing on high-risk groups such as patients with early disease, elevated CRP, syndesmophytes at baseline, male patients and patients with HLA-B27 + are promising options for the near future. However, for optimal prevention of formation of syndesmophytes we need more detailed insight in the pathogenesis of bone formation in axSpA and probably more targeted therapies.

ObjectivemiRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients.MethodsExpression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population.ResultsA total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P ConclusionmiRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.

MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs which regulate gene expression. They originate from various tissues including bone and regulate different biological mechanisms including bone metabolism.The aim of this project was to investigate circulating miRNAs as promising biomarkers for treatment monitoring in women with postmenopausal osteoporosis on denosumab (DMAB) therapy.In this prospective, observational, single-centre study twenty-one postmenopausal women treated with DMAB were included for a longitudinal follow-up of two years.Next-generation sequencing (NGS) was performed to screen for serological miRNAs at defined time points (baseline, month 6 and month 24). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to confirm NGS findings in the entire cohort. Bone turnover markers (BTM) P1NP and CTX, and bone mineral density (BMD) by Dual X-Ray absorptiometry (DXA) were assessed and correlated to miRNAs.BMD at the hip (5,5%, p = 0.0006) and lumbar spine significantly increased (11,4%, p-value = 0.017) and CTX (64,1%, p 0.0001) and P1NP (69,3%, p 0.0001) significantly decreased during treatment. NGS analysis revealed significant changes in miRNAs after 2-years of DMAB treatment, but not after 6-months. Seven miRNAs were confirmed by RT-qPCR to be significantly changed during a 2-year course of DMAB treatment compared to baseline. Four of these were found to be mainly transcribed in blood cells including monocytes. Correlation analysis identified a significant correlation between change in miRNA and change in BTMs as well as BMD. Based on effect size and correlation strength, miR-454-3p, miR-26b-5p and miR-584-5p were defined as top biomarker candidates with the strongest association to the sustained effect of denosumab on bone in osteoporotic patients.Two years of DMAB-treatment resulted in the upregulation of 7 miRNAs, four of which are mainly transcribed in monocytes indicating a potential impact of DMAB on circulating osteoclast precursor cells. These changes were associated to BMD gain and BTM suppression and could therefore be useful for monitoring DMAB-treatment response.

Objective Patients with diabetes have an increased risk of osteoporosis and shorter life expectancy. Hip fracture (HF) is the most serious consequence of osteoporosis and is associated with increased mortality risk. We aimed to assess the association of antidiabetic medications with HF and the post-hip fracture mortality risk among diabetic patients ≥50 years. Design In this nationwide case-control study 53 992 HF cases and 112 144 age-, sex- and region-matched non-hip fracture controls were analyzed. A cohort of hip-fractured diabetic patients were followed-up for an all-cause mortality. Methods We defined three groups of diabetic patients based on a prescription of antidiabetic medications: group 1 treated with insulin monotherapy (G1DM), group 2 (G2DM) treated with blood glucose-lowering drugs (BGLD) only, group 3 on a combined BGLD and insulin therapy (G3DM). We applied logistic regression and Cox regression. Results We identified 2757 G1DM patients, 15 310 G2DM patients, 3775 G3DM patients and 144 294 patients without any antidiabetic treatment. All three groups of diabetic patients had increased odds of HF compared to controls. G1DM patients aged 50–64 years (aOR: 4.80, 95% CI: 3.22–7.17) and G3DM patients (aOR: 1.39, 95% CI: 1.02–1.88) showed the highest HF odds, whereas G2DM patients had 18% decrease in HF odds than their non-diabetic controls (aOR: 0.82, 95% CI: 0.69–0.99). All diabetic patients had increased post-hip fracture mortality risk compared to non-diabetic controls. The highest mortality hazard was observed in G1DM patients, being greater for women than men (HR: 1.71, 95% CI: 1.55–1.89 and HR: 1.44, 95% CI: 1.27–1.64, respectively). Conclusions Antidiabetic medications increase the probability of HF. Diabetic patients, who sustained HF have a higher mortality risk than non-diabetic patients.

MicroRNAs regulate bone homeostasis, and circulating microRNAs have been proposed as novel bone biomarkers. The effect of anti‐osteoporotic treatment on circulating microRNAs has not been described in detail. Therefore, we performed a comprehensive analysis of microRNA serum levels in ovariectomized (OVX) and sham‐operated (SHAM) rats over 12 weeks of antiresorptive or osteoanabolic treatment. Forty‐two Sprague Dawley rats underwent SHAM surgery (n = 10) or ovariectomy (n = 32). After 8 weeks, OVX rats were randomized to antiresorptive treatment with zoledronate (n = 11), osteoanabolic treatment with teriparatide (n = 11), or vehicle treatment (n = 10). Serum samples were collected at weeks 8, 12, 16, and 20 after surgery. A total of 91 microRNAs were analyzed by RT‐qPCR in serum samples collected at week 20. Based on the results, 29 microRNAs were selected for longitudinal analysis at all four study time points. Changes in bone mineral density and microstructure were followed up by in vivo micro‐CT and ex vivo nano‐CT. Ovariectomy resulted in the loss of trabecular bone, which was reversed by osteoanabolic and antiresorptive treatment. Differential expression analysis identified 11 circulating miRNAs that were significantly regulated after treatment. For example, miR‐107 and miR‐31‐5p increased in vehicle‐treated OVX animals, whereas they decreased during teriparatide treatment. Additional miRNAs were identified that showed significant correlations to bone microstructure or bone miRNA expression, including miR‐203a‐3p, which exhibited a significant negative correlation to vertebral and tibial trabecular bone volume fraction (%). Longitudinal analysis confirmed eight microRNAs with significant changes in serum over time that were prevented by teriparatide and zoledronate treatment (miR‐34a‐5p, miR‐31‐5p, miR‐30d‐3p, miR‐378a‐5p) or teriparatide treatment only (miR‐375‐3p, miR‐183‐5p, miR‐203a‐3p, miR‐203b‐3p). Gene target network analysis identified WNT and Notch signaling as the main signaling pathways controlled by these miRNAs. Thus, ovariectomy results in time‐dependent deregulation of circulating miRNAs compared with SHAM animals. Anti‐osteoporotic treatments can rescue this effect, showing that bone‐related miRNAs might act as novel biomarkers for treatment monitoring. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

In recent years, new treatment options for both common and rare bone diseases have become available. The sclerostin antibody romosozumab is the most recently approved drug for the therapy of postmenopausal osteoporosis. Its anabolic capacity makes it a promising treatment option for severe osteoporosis. Other sclerostin antibodies for the treatment of rare bone diseases such as osteogenesis imperfecta are currently being investigated. For rare bone diseases such as X‑linked hypophosphatemia (XLH) and hypophosphatasia (HPP), specific therapies are now also available, showing promising data in children and adults with a severe disease course. However, long-term data are needed to assess a sustained benefit for patients.Neue therapeutische Möglichkeiten zur Therapie der Osteoporose, aber auch seltener Knochenerkrankungen stehen neuerdings zu Verfügung. Der Sclerostin-Antikörper Romosozumab wurde unlängst zur Behandlung der postmenopausalen Osteoporose zugelassen. Durch seine osteoanabole Wirkung scheint Romosozumab eine vielversprechende Therapieoption der schweren Osteoporose zu sein. Andere Sclerostin-Antikörper werden derzeit bei seltenen Knochenerkrankungen wie der Osteogenesis imperfecta untersucht. Für den Phosphatdiabetes („X-linked hypophosphatemia“, XLH) und die Hypophosphatasie (HPP) stehen nun spezifische Therapien zur Verfügung, die in den bisherigen Studien überzeugende Ergebnisse zeigten. Langzeitdaten sind jedoch erforderlich, um das Risiko-Nutzen-Profil abschätzen zu können.

(1) Background: Pelvic fractures (PFs) are related to osteoporosis, and represent a serious individual and socioeconomic burden. (2) Methods: We examined age- and sex-standardised incidence rates (SIRs) of PF, along with rates of all-cause overall and one-year mortality among patients with PF. We compared the mortality rates between PF patients and a matched fracture-free cohort. Patients ≥50 years old in Austria hospitalised with PF in 2010–2018, along with their dates of death, were recorded. (3) Results: We identified 54,975 patients with PF, of whom 70.9% were women. Between 2010 and 2018 the SIR of PF increased in men by 10.0%—from 125.3 (95% Confidence Interval 118.9–132.0) to 137.8 (95% CI 131.8–144.0) per 100,000—and in women by 2.7%—from 218.7 (95% CI 212.0–225.6) to 224.7 (95% CI 218.3–231.3) per 100,000. The one-year post-PF mortality rate was higher in men than in women (13.0% and 11.1%, respectively; p < 0.001). Pelvic fracture patients aged ≥65 had an elevated mortality risk (Hazard Ratio 1.75, 95% CI 1.71–1.79, p < 0.001) compared to controls. (4) Conclusions: There is a clear increase in the incidence of PF in the elderly population, with a greater increase in men over time. Pelvic fracture itself contributes to increased mortality in individuals aged 65 and above.

Caring for osteoporosis patients has proven challenging during the COVID-19 pandemic due to repeated lockdowns in Austria. The distinct possibility of insufficient treatment regimens is therefore a matter of pressing concern. The aim of the study was to assess alterations in dispensing anti-osteoporotic drugs during the COVID-19 pandemic.This study was a nationwide retrospective register-based observational study which included all patients in Austria aged ≥50 who received at least one prescription for anti-osteoporotic medication between January 2016 and November 2020. Pseudonymised individual-level patients' data were obtained from social insurance authorities. Anti-osteoporotic agents were divided into: (i) oral bisphosphonates, (ii) intravenous bisphosphonates, (iii) selective estrogen receptor modulators (SERMs), (iv) teriparatide (TPTD) and (v) denosumab (DMAB). We used interrupted time series analysis with autoregressive integrated moving average models (ARIMA) to predict drug dispensing.There were 2,884,374 dispensations of anti-osteoporotic drugs to 224,598 patients between 2016 and 2020. The mean monthly prescriptions for oral bisphosphonates (-14.5 %) and SERMs (-12.9 %) decreased during the COVID-19 pandemic when compared to the non-COVID-19 period. Dispensing for intravenous bisphosphonates (1.7 %) and teriparatide (9.5 %) increased. Prescriptions for DMAB decreased during the first lock-down, however increased by 29.1 % for the total observation time. The Arima models showed that in March 2020 (beginning of the 1st COVID-19 lockdown), there was a decrease of 778 dispensings, with a further increase of 14 dispensings every month for denosumab; a decrease by 178 dispensings, with a further increase of 23 dispensings every month for zolendronic acid; a decrease by 2950 dispensings, but with a further increase of 236 dispensings every other month for ibandronate and a decrease by 1443 dispensing with a further decrease of 29 dispensings for alendronate than predicted, had the lockdown not occurred.The total number of prescriptions dispensed to patients treated with anti-osteoporotic medications declined rapidly during first COVID-19 lockdown. The observed decrease of DMAB during the first lockdown rebounded in the following months. Considering the massive treatment gap for osteoporosis, and the related fracture risk, clinicians should continue treatment, even during a pandemic.

Background and Aims With rising rates of inflammatory bowel diseases [IBD] in older adults, management of comorbidities such as osteoporosis is becoming increasingly important. Hip fracture [HF] is the most serious consequence of low bone mineral quality and is associated with excess risk of mortality. For older IBD patients, there are only limited data available. Therefore, we aimed to assess the association of IBD with HF, and all-cause mortality risk after HF, among IBD patients older than 50 years. Methods In a national database-registered case-control study, 56 821 HF cases aged ≥50 years, and 113 718 age-, sex- and region-matched non-hip-fracture controls, were analysed between 2012 and 2016. A history of IBD was assessed from data from Austrian social health insurance funds. Logistic regression and Cox proportional multivariate models were used to test the association of IBD with HF and post-hip fracture mortality risk. Results A total of 531 patients were identified with IBD (25.0% men, mean age 81.2 years, standard deviation [SD] 9.7). Analysis, adjusted for anti-osteoporotic treatment, use of glucocorticoids, and selected medications, showed that IBD patients had an increased odds of HF (odds ratio [[OR] 2.22, 95% confidence interval [CI] 1.86–2.64). Patients with Crohn’s disease [CD] revealed a higher HF odds in contrast to patients with ulcerative colitis [OR 2.91, 95% CI 2.17–3.89 and OR 1.89, 95% CI 1.52–2.35, respectively]. Overall mortality risk after HF was higher among female CD patients [HR 1.75, 95% CI 1.28–2.41] than in the general population. Conclusions IBD was strongly associated with HF in older patients. Post-hip fracture mortality risk was elevated particularly in women with CD.

A 73-year-old male patient presented with a 3-month history of back pain. In bone scintigraphy and the FDG PET-CT scan (fluorodeoxyglucose positron-emission computed tomography), highly suspect uptake levels were found in TH12-L1. Accordingly, an osteodestructive process was found on MRI (magnetic resonance imaging). Following a successfully performed biopsy of TH12, histologic analysis of the bone material revealed a chondrosarcoma (G1; T4N2M0). Complete resection of the tumor was successfully performed, since chondrosarcoma are resistant to radiation and chemotherapy.As chondrosarcoma is a rare bone neoplasm, it must be considered in the differential diagnosis of lower back pain to initiate adequate treatment.

Purpose The aim of this study was to investigate the effect of extracorporeal shockwave therapy (ESWT) on bone microstructure as well as the bone-tendon-interface and the musculo-tendinous transition zone to explain the previously shown improved biomechanics in a degenerative rotator cuff tear animal model. This study hypothesized that biomechanical improvements related to ESWT are a result of improved bone microstructure and muscle tendon properties. Methods In this controlled laboratory study unilateral supraspinatus (SSP) tendon detachment was performed in 48 male Sprague-Dawley rats. After a degeneration period of three weeks, SSP tendon was reconstructed transosseously. Rats were randomly assigned into three groups (n = 16 per group): control (noSW); intraoperative shockwave treatment (IntraSW); intra- and postoperative shockwave treatment (IntraPostSW). Eight weeks after SSP repair, all rats were sacrificed and underwent bone microstructure analysis as well as histological and immunohistochemical analyses. Results With exception of cortical porosity at the tendon area, bone microstructure analyses revealed no significant differences between the three study groups regarding cortical and trabecular bone parameters. Cortical Porosity at the Tendon Area was lowest in the IntraPostSW (p≤0.05) group. Histological analyses showed well-regenerated muscle and tendon structures in all groups. Immunohistochemistry detected augmented angiogenesis at the musculo-tendinous transition zone in both shockwave groups indicated by CD31 positive stained blood vessels. Conclusion In conclusion, bone microarchitecture changes are not responsible for previously described improved biomechanical results after shockwave treatment in rotator cuff repair in rodents. Immunohistochemical analysis showed neovascularization at the musculo-tendinous transition zone within ESWT-treated animals. Further studies focusing on neovascularization at the musculo-tendinous transition zone are necessary to explain the enhanced biomechanical and functional properties observed previously. Clinical relevance In patients treated with a double-row SSP tendon repair, an improvement in healing through ESWT, especially in this area, could prevent a failure of the medial row, which is considered a constantly observed tear pattern.

ObjectiveTo compare the effects of interleukin-6 (IL-6) receptor and tumour necrosis factor inhibition on inducing repair of existing bone erosions in patients with very early rheumatoid arthritis (RA).MethodsProspective non-randomised observational study in patients with active erosive RA with inadequate response to methotrexate (MTX) receiving either tocilizumab (TOC) monotherapy or adalimumab (ADA) with MTX for 52 weeks. Erosion volumes were assessed in metacarpal heads (MCH) and the radius by high-resolution peripheral quantitative CT at baseline and after 52 weeks. Clinical response was monitored using Clinical Disease Activity Index, Simple Disease Activity Index and Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) scores every 12 weeks.ResultsTOC (N=33) and ADA/MTX (N=33) treatment groups were balanced for age, sex, body mass index, comorbidities, disease and activity, functional state, autoantibody status, baseline bone damage and baseline bone biomarkers. Both TOC (DAS28-ESR: baseline: 6.2±0.5; 52 weeks: 2.3±1.0) and ADA/MTX (6.3±0.6; 2.8±1.2) significantly reduced disease activity. Erosion volumes significantly decreased in the MCH and radius of patients with RA treated with TOC (p3 and −3.3±5.9 mm3 in the MCH and radius of TOC-treated patients, respectively, and −0.05±0.9 mm3 and −0.08±4.1 mm3 in patients treated with ADA/MTX.ConclusionsThe REBONE study shows that TOC monotherapy achieves more pronounced repair of existing bone erosions than ADA/MTX. Hence, IL-6 is a central factor for the disturbed bone homeostasis in the joints of patients with RA.

Hypophosphatasie (HPP) ist eine seltene genetische Erkrankung, die durch eine reduzierte Aktivitat der alkalischen Phosphatase (ALP) charakterisiert ist. Das klinische Bild ist auserst variabel. Oft erfolgt die Diagnose spat, da die Symptome anderen, vor allem rheumatologischen oder osteologischen Erkrankungen ahneln. Asfotase alfa ist eine Enzymersatztherapie, die bei Patienten indiziert ist, bei denen die HPP im Kindes- und Jugendalter aufgetreten ist, um die Knochenmanifestationen zu behandeln. Antiresorptive Medikamente sind bei HPP kontraindiziert.

Summary Liver cirrhosis leads to bone loss. To date, information on bone quality (three-dimensional microarchitecture) and, thus, bone strength is scarce. We observed decreased bone quality at both assessed sites, independent of disease severity. Therefore, all patients should undergo early-stage screening for osteoporosis. Introduction Recent studies found low bone mineral density in cirrhosis, but data on bone microstructure are scarce. This study assessed weight-bearing and non-weight-bearing bones in patients with cirrhosis and healthy controls. The primary objective was to evaluate trabecular and cortical microarchitecture. Methods This was a single-center study in patients with recently diagnosed hepatic cirrhosis. Thirty-two patients and 32 controls participated in this study. After determining the type of cirrhosis, the parameters of bone microarchitecture were assessed by high-resolution peripheral quantitative computed tomography. Results Both cortical and trabecular microarchitectures showed significant alterations. At the radius, trabecular bone volume fraction was 17% lower (corrected p = 0.028), and, at the tibia, differences were slightly more pronounced. Trabecular bone volume fraction was 19% lower (p = 0.024), cortical bone mineral density 7% (p = 0.007), and cortical thickness 28% (p = 0.001), while cortical porosity was 32% higher (p = 0.023), compared to controls. Areal bone mineral density was lower (lumbar spine − 13%, total hip − 11%, total body − 9%, radius − 17%, and calcaneus − 26%). There was no correlation between disease severity and microarchitecture. Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) correlated well with parameters of cortical and trabecular microarchitecture. Conclusions Hepatic cirrhosis deteriorates both trabecular and cortical microarchitecture, regardless of disease severity. Areal bone mineral density is diminished at all sites as a sign of generalized affection. In patients with hepatic cirrhosis, regardless of its origin or disease severity, aBMD measurements are an appropriate tool for osteologic screening.

Multiple fractures are of high clinical relevance, as a significant increase in mortality rate has been described. The purpose of this study was to evaluate differences in age and gender distribution in multiple fractures dependent on severity of trauma. Furthermore, affected anatomic regions and frequently associated fracture regions were investigated. Patients who had sustained multiple fractures between 2000 and 2012 were included in this study. At hospital admission, patients were divided according to trauma severity (high- vs low-traumatic), gender, and age for demographic analysis. Fractures were grouped in anatomical regions, and multiple fracture event probabilities as well as frequently associated regions were calculated. In total, 25,043 patients at an age range of 0–100 years (5.8% of all fracture patients; 14,769 male and 10,274 female patients) who sustained 57,862 multiple fractures were included. The lumbar/thoracic spine, cervical spine, femoral shaft, skull, and pelvis showed a probability of more than 40% of the presence of further fractures in each high-traumatic fracture event. In high-traumatic fracture events, male patients were more affected (p

BACKGROUND: Hypophosphatasia (HPP) is a rare hereditary disorder characterized by defective bone and tooth mineralization caused by mutations in the alkaline phosphatase (ALPL) gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Here we performed clinical and molecular studies on 5 HPP children to investigate the pathogenic mechanisms of the ALPL gene variants. METHODS: Clinical and genetic analyses were performed on 5 HPP children, and the loci where ALPL variants were identified. Plasmids containing the relevant loci were constructed. The molecular and cellular mechanisms of the pathogenic ALPL variants were investigated by cellular immunofluorescence, enzyme activity assay, and protein expression assay. RESULTS: A total of 6 ALPL variants were identified in 5 HPP children: proband 1: c.346G>A (p.A116T); proband 2: c.346G>A (p.A116T)/deletions from c.1097 to c.1099 CCT (p.T366_S367deli) compound heterozygous variant; proband 3: insertion of G from c.1014 to c.1015 (p.H338fs)/c.1446C>A (p.H482Q) compound heterozygous variant; proband 4: c.920C>T (p.P307L); and proband 5: c.883A>G (p.M295V). Twenty-four hours after the HEK-293T was transfected with different variant plasmids, its alkaline phosphatase activity and enzyme protein content were reduced compared with the wild type, and there were differences among different variants. Except for 1014-G-1015+C1446A, the degree of reduction in enzyme activity was negatively correlated with the severity of clinical manifestations. Immunofluorescence revealed that the variants (especially c.883A>G and c.920C>T) caused a decrease in alkaline phosphatase expression in the cellular membrane. CONCLUSIONS: In total, 3 novel variants were identified in these 5 HPP children, the discovery of which will enrich the human ALPL gene mutation database. Different variants in the ALPL gene can downregulate the activity of TNSALP enzyme (and thus affect its function) by affecting protein expression and translational modifications. The same variant may cause clinical manifestations of different severities in different individuals due to the presence of dominant negative effects, alterations in noncoding sequences, blind area of intron regulatory region sequencing, and variations in environmental and individual factors. The molecular mechanisms via which the ALPL gene exerts its expression effect in vivo are highly variable and warrant further investigation.

Tenofovir is a nucleotide analog reverse‐transcriptase inhibitor (NtARTI) used for treatment of chronic hepatitis B and human immunodeficiency virus (HIV). Fanconi syndrome (FS) is a condition affecting the proximal tubules of the kidney, leading to increased passage and impaired reabsorption of various small molecules such as glucose, phosphate, bicarbonate, and amino acids. Tenofovir disoproxil fumarate (TDF) is one of two pro‐drugs of tenofovir associated with a greater nephrotoxicity and renal complications such as FS with subsequent osteomalacia, acute kidney injury, and reduction of glomerular filtration rate (GFR) compared with tenofovir alafenamide (TAF). We present the case of a 33‐year‐old white woman treated with TDF because of chronic hepatitis B infection suffering four atraumatic fractures over the period of 2 years. The patient was taken off the TDF regimen 3 months before presentation. Initial blood and urine samples suggested the presence of TDF‐induced osteomalacia, which was confirmed by transiliac bone biopsy and histomorphometry. Moreover, bone mineral density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) analysis showed that approximately 56% of the bone surface was normally mineralized and 44% showed a reduced mineralization consistent with the presence of osteomalacia. The patient made a significant recovery upon cessation of the causative agent. This case report emphasizes the use of bone biopsy, histomorphometry and qBEI in confirming the diagnosis of drug‐induced Fanconi syndrome and associated osteomalacia. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

BackgroundThis study aimed to investigate whether rodent shoulder specimens fixed in formaldehyde for histological and histomorphometric investigations and specimens stained using Lugol’s solution for soft tissue visualization by micro-computed tomography (microCT) are still eligible to be used for bone architecture analysis by microCT.MethodsIn this controlled laboratory study, 11 male Sprague-Dawley rats were used. After sacrifice and exarticulation both shoulders of healthy rats were assigned into three groups: (A) control group (n= 2); (B) formaldehyde group (n= 4); (C) Lugol group (n= 5). Half of the specimens of groups B and C were placed in a 4% buffered formaldehyde or Lugol’s solution for 24 h, whereas the contralateral sides and all specimens of group A were stored without any additives. MicroCT of both sides performed in all specimens focused on bone mineral density (BMD) and bone microstructure parameters.ResultsBMD measurements revealed higher values in specimens after placement in Lugol’s solution (p< 0.05). Bone microstructure analyses showed increased BV/TV and Tb.Th values in group C (p< 0.05). Specimens of group C resulted in clearly decreased Tb.Sp values (p< 0.05) in comparison to the control group. Formaldehyde fixation showed minimally altered BMD and bone microstructure measurements without reaching any significance.ConclusionsMicroCT scans of bone structures are recommended to be conducted natively and immediately after euthanizing rats. MicroCT scans of formaldehyde-fixed specimens must be performed with caution due to a possible slight shift of absolute values of BMD and bone microstructure. Bone analysis of specimens stained by Lugol’s solution cannot be recommended.

Crohn&rsquo, s disease (CD) is associated with bone loss and increased fracture risk. TX-Analyzer&trade, is a new fractal-based technique to evaluate bone microarchitecture based on conventional radiographs. The aim of the present study was to evaluate the TX-Analyzer&trade, of the thoracic and lumbar spine in CD patients and healthy controls (CO) and to correlate the parameters to standard imaging techniques. 39 CD patients and 39 age- and sex-matched CO were analyzed. Demographic parameters were comparable between CD and CO. Bone structure value (BSV), bone variance value (BVV) and bone entropy value (BEV) were measured at the vertebral bodies of T7 to L4 out of lateral radiographs. Bone mineral density (BMD) and trabecular bone score (TBS) by dual energy X-ray absorptiometry (DXA) were compared to TX parameters. BSV and BVV of the thoracic spine of CD were higher compared to controls, with no difference in BEV. Patients were further divided into subgroups according to the presence of a history of glucocorticoid treatment, disease duration &gt, 15 years and bowel resection. BEV was significantly lower in CD patients with these prevalent risk factors, with no differences in BMD at all sites. Additionally, TBS was reduced in patients with a history of glucocorticoid treatment. Despite a not severely pronounced bone loss in this population, impaired bone quality in CD patients with well-known risk factors for systemic bone loss was assessed by TX-Analyzer&trade

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by impaired bone quality and quantity. Established imaging techniques have limited reliability in OI. The TX-Analyzer™ is a new, fractal-based software allowing a non-invasive assessment of bone structure based on conventional radiographs. We explored whether the TX-Analyzer™ can discriminate OI patients and healthy controls. Furthermore, we investigated the correlation between TX-Analyzer™ parameters and (i) bone mineral density (BMD) by Dual Energy X-ray Absorptiometry (DXA), (ii) trabecular bone score (TBS), and (iii) bone microstructure by high-resolution peripheral quantitative computed tomography (HR-pQCT).Data of 29 adult OI patients were retrospectively analyzed. Standard radiographs of the thoracic and lumbar spine were evaluated using the TX-Analyzer™. Bone Structure Value (BSV), Bone Variance Value (BVV), and Bone Entropy Value (BEV) were measured at the vertebral bodies T7 to L5. Data were compared to a healthy, age- and gender-matched control group (n = 58). BMD by DXA, TBS, and trabecular bone microstructure by means of HR-pQCT were correlated to TX-Analyzer™ parameters in OI patients. The accuracy of the TX-Analyzer™ parameters in detecting OI was assessed with area under curve (AUC) analysis of receiver operating characteristic (ROC).BEV of the thoracic and the lumbar spine were significantly lower in OI patients compared to controls (both p 0.001). BEV of the thoracic spine was significantly correlated to TBS (ρ = 0.427, p = 0.042) as well as trabecular number (Tb.N) at the radius (ρ = 0.603, p = 0.029) and inhomogeneity of the trabecular network (Tb.1/N.SD) at the radius (ρ = -0.610, p = 0.027), when assessed by HR-pQCT. No correlations were found between BEV and BMD by DXA. BEV of the thoracic and the lumbar spine had an AUC of 0.81 (95% confidence interval [CI] 0.67-0.94, p 0.001) and 0.73 (95% CI 0.56-0.89, p = 0.008), respectively. BSV and BVV did not differ between OI patients and controls.The software TX-Analyzer™ is able to discriminate patients with OI from healthy controls. ROC curves of BEV values suggest a suitable clinical applicability. Low to no correlations with conventional methods suggest, that the TX-Analyzer™ may indicate a new and independent examination tool in OI.

Numerous safe and efficient drug therapies are currently available to decrease risk of low trauma fractures in patients with osteoporosis including postmenopausal, male, and secondary osteoporosis. In this chapter, we give first an overview of the most important outcomes regarding fracture risk reduction, change in bone mineral density (BMD by DXA) and/or bone markers of the phase III clinical studies of well-established therapies (such as Bisphosphonates, Denosumab or Teriparatide) and also novel therapies (such as Romosozumab or Abaloparatide) and highlight their mechanisms of action at bone tissue/material level. The latter understanding is not only essential for the choice of drug, duration and discontinuation of treatment but also for the interpretation of the clinical outcomes (in particular of eventual changes in BMD) after drug administration. In the second part of this chapter, we focus on the management of different forms of osteoporosis and give a review of the respective current guidelines for treatment. Adverse effects of treatment such as atypical femoral fractures, osteonecrosis of the jaw or influence of fracture healing are considered also in this context.

X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.