Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis.

OBJECTIVE: miRNAs 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. METHODS: Expression 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. RESULTS: A 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 < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. CONCLUSION: miRNA 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.

Chondrosarcoma of the spine-a case report.

CASE: 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. CONCLUSION: As chondrosarcoma is a rare bone neoplasm, it must be considered in the differential diagnosis of lower back pain to initiate adequate treatment.

Circulating miRNAs Respond to Denosumab Treatment After 2 Years in Postmenopausal Women With Osteoporosis-the MiDeTe study.

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.

Metabolic Bone Diseases-A Topic of Great Diversity.

The progress in research has improved the understanding of the epidemiology and pathogenesis of osteoporosis and bone disorders in general [...].

Dispensing anti-osteoporotic drugs changed during the COVID-19 pandemic.

OBJECTIVES: 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. PATIENTS/METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pelvic Fractures-An Underestimated Problem? Incidence and Mortality Risk after Pelvic Fracture in Austria, 2010-2018.

(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 100,000­and 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.

Attenuation of COVID-19-induced cytokine storm in a young male patient with severe respiratory and neurological symptoms.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), produces protean manifestations and causes indiscriminate havoc in multiple organ systems. This rapid and vast production of proinflammatory cytokines contributes to a condition termed cytokine storm. A 35-year-old, otherwise healthy, employed, male patient was tested positive for COVID-19. He was admitted to the hospital on disease day 10 due to retarded verbal reactions and progressive delirium. On account of these conditions and the need for noninvasive/invasive ventilation, a combination treatment with baricitinib and remdesivir in conjunction with standard of care was initiated. The cytokine storm was rapidly blocked, leading to a vast pulmonary recovery with retarded recovery of the central nervous system. We conclude that the rapid blockade of the COVID-19-induced cytokine storm should be considered of avail as a principle of careful decision-making for effective recovery.

Analysis of bone architecture using fractal-based TX-Analyzer™ in adult patients with osteogenesis imperfecta.

BACKGROUND: 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). MATERIAL AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Treatment of hypophosphatasia.

Hypophosphatasia (HPP) is a rare disorder with perinatal, infantile, childhood, and adult presentations. Severe forms are autosomal recessive with an early onset, whereas milder forms have a later onset. The underlying cause of the disease is a mutation based on a genetic disorder of the tissue non-specific alkaline phosphatase (TNSALP) gene, leading on the one hand to decreased activity of the TNSALP enzyme, and on the other hand to accumulation of TNSALP substrates. Symptoms like non-traumatic and non-healing fractures, musculoskeletal pain, chondrocalcinosis, seizures, premature loss of fully rooted teeth or delayed development of milk teeth, respiratory insufficiency, and calcinosis in muscles, kidneys, and joints occur. Supportive treatment is important for HPP patients, including mechanical ventilation, accurate fracture treatment, physical therapy, dental monitoring, and follow-up care to avoid subsequent problems. A causal enzyme therapy replacement with asfotase-alfa was approved by the Food and Drug Administration (FDA) in 2015. Asfotase-alfa improves respiratory insufficiency, bone mineralization, and long-term survival, and has a very good safety profile.

Correction to: Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis.

Correction to: Wien Klin Wochenschr 2019 https://doi.org/10.1007/s00508-019-01595-8 The original version of this article unfortunately contained a mistake. The last sentence should read: Patients with ALD had significantly lower sclerostin levels, compared to controls. The authors apologize for the ….

Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis.

BACKGROUND: Patients with hepatic cirrhosis are at increased risk of bone loss. Recent work on areal bone mineral density has reported contradictory findings. As the assessment of bone microarchitecture is complex, a search was made for correlations with new serum markers of bone turnover. Current data on serum sclerostin levels in patients with increased fracture risk are divergent and to date only one study has examined patients with hepatic cirrhosis. Therefore, the aim of this study was to evaluate serum sclerostin levels and to test for correlations with microarchitecture. METHODS: This study was performed in 32 patients with recently diagnosed hepatic cirrhosis and 32 controls. The parameters of bone microarchitecture were assessed by high-resolution peripheral quantitative computed tomography. Sclerostin was detected via a new ELISA that detects the active receptor interaction site at loop 2 of the sclerostin core region. RESULTS: Sclerostin levels were slightly, but not significantly lower in the patient group, compared to controls. In contrast, patients with alcoholic liver cirrhosis had significantly lower levels than the controls. A significant correlation with areal bone mineral density (BMD) and trabecular microarchitecture was observed in the patient group. However, there was hardly any correlation between sclerostin and bone microarchitecture in the controls. CONCLUSION: In hepatic cirrhosis, sclerostin is related to altered bone microarchitecture and lower areal BMD. In alcoholic liver disease, low sclerostin concentrations were seen.

Fracture patterns in patients with multiple fractures: the probability of multiple fractures and the most frequently associated regions.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 < 0.001). Considering low-traumatic fractures, female patients had a significantly higher proportion (p < 0.001) of multiple fractures among all fractures than male patients. CONCLUSIONS: As a novelty, gender as well as age distributions in multiple fracture patients and a probability statement with the most affected anatomic regions, the risk of presence of further fractures for every region, and the frequently associated fracture regions including the percentage of occurrence are provided. These aspects yield new opportunities for clinical work and may reduce the high rate of overlooked fractures stated in the literature.

Bone Stress Injuries Are Associated With Differences in Bone Microarchitecture in Male Professional Soldiers.

Bone stress injuries are commonly due to repetitive loading, as often described in competitive athletes or military recruits. The underlying pathophysiology of bone stress injuries is multifactorial. The present cross-sectional study investigated (i) cortical and trabecular bone microstructure as well as volumetric bone mineral density in subjects with bone stress injuries at the tibial diaphysis, measured at the distal tibia and the distal radius by means of high-resolution peripheral quantitative computed tomography (CT), (ii) areal bone mineral density using dual-energy X-ray absorptiometry as well as calcaneal dual X-ray absorptiometry and laser, and (iii) the influence on bone turnover markers of formation and resorption at the early phase after injury. A total of 26 Caucasian male professional soldiers with post-training bone stress injury at the tibial diaphysis were included (case group). A total of 50 male, Caucasian professional soldiers from the same military institution served as controls (control group). High-resolution peripheral quantitative CT revealed a higher total area at the radius within the case group. Cortical bone mineral density was reduced at the radius and tibia within the case group. The trabecular number and trabecular thickness were reduced at the tibia in the case group. The trabecular network was more inhomogeneous at the radius and tibia within the case group. Calcaneal dual X-ray absorptiometry and laser was significantly reduced in the case group. This study quantified differences in bone microstructure among otherwise healthy individuals. Differences in bone microarchitecture may impair the biomechanical properties by increasing the susceptibility to sustain bone stress injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2516-2523, 2019.

Hypophosphatasia: From Diagnosis to Treatment.

PURPOSE OF REVIEW: Hypophosphatasia (HPP) is a rare genetic disorder caused by mutations of the ALPL gene. ALPL encodes the tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Consequently, bone mineralization is decreased leading to fractures, arthralgia, and extra-skeletal manifestations including tissue calcification, respiratory failure, and neurological complications. This review summarizes the most important clinical findings, diagnosis, and treatment options for HPP. RECENT FINDINGS: Asfotase alfa is a recombinant human alkaline phosphatase, used as treatment for the underlying cause of HPP. Asfotase alfa enhances the survival in life-threatening HPP and improves bone mineralization, muscle strength, and pulmonary function. However, discontinuation of asfotase alfa leads to reappearance of bone hypomineralization. Due to its varied manifestations, HPP often mimics rheumatological and other bone diseases, thereby delaying its diagnosis. Asfotase alfa, a recombinant alkaline phosphatase, is available for the long-term enzyme replacement therapy in patients with pediatric-onset HPP to treat the bone manifestations of the disease.

Cortical bone loss is an early feature of nonradiographic axial spondyloarthritis.

BACKGROUND: In the present study, we investigated bone geometry, microstructure, and volumetric bone mineral density (vBMD) in a cohort of patients with nonradiographic axial spondyloarthritis (nr-axSpA) in order to define the early bone changes occurring in axial spondyloarthritis (axSpA) and to define potential factors for deterioration of bone microstructure. METHODS: Patients with axSpA (n = 107) and healthy control subjects (n = 50) of similar age and sex were assessed for geometric, volumetric, and microstructural parameters of bone using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius. Additionally, demographic and disease-specific characteristics of patients with axSpA were recorded. RESULTS: Patients with nr-axSpA and control subjects were comparable in age, sex, and body mass index. Geometric and microstructural analysis by HR-pQCT revealed a significantly reduced cortical area (p = 0.022) and cortical thickness (p = 0.006) in patients with nr-axSpA compared with control subjects. Total and cortical vBMD were significantly reduced in patients with nr-axSpA (p = 0.042 and p = 0.007, respectively), whereas there was no difference in trabecular vBMD. Patients with a short disease duration (< 2 years; n = 46) also showed significant reduction of cortical thickness and cortical area compared with control subjects. Patients with disease duration > 2 years (n = 55) additionally developed a decrease of cortical and total vBMD. Multiple regression models identified male sex to be associated with lower cortical vBMD and female sex to be associated with lower trabecular vBMD. CONCLUSIONS: Bone microstructure in patients with nr-axSpA is characterized primarily by deterioration of cortical bone. Cortical bone loss starts early and is evident within the first 2 years of the disease.

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study.

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤-2.0 and ≥-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker ß-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and ß-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Bone-related Circulating MicroRNAs miR-29b-3p, miR-550a-3p, and miR-324-3p and their Association to Bone Microstructure and Histomorphometry.

The assessment of bone quality and the prediction of fracture risk in idiopathic osteoporosis (IOP) are complex prospects as bone mineral density (BMD) and bone turnover markers (BTM) do not indicate fracture-risk. MicroRNAs (miRNAs) are promising new biomarkers for bone diseases, but the current understanding of the biological information contained in the variability of miRNAs is limited. Here, we investigated the association between serum-levels of 19 miRNA biomarkers of idiopathic osteoporosis to bone microstructure and bone histomorphometry based upon bone biopsies and µCT (9.3 µm) scans from 36 patients. Four miRNAs were found to be correlated to bone microarchitecture and seven miRNAs to dynamic histomorphometry (p < 0.05). Three miRNAs, namely, miR-29b-3p, miR-324-3p, and miR-550a-3p showed significant correlations to histomorphometric parameters of bone formation as well as microstructure parameters. miR-29b-3p and miR-324-p were found to be reduced in patients undergoing anti-resorptive therapy. This is the first study to report that serum levels of bone-related miRNAs might be surrogates of dynamic histomorphometry and potentially reveal changes in bone microstructure. Although these findings enhance the potential value of circulating miRNAs as bone biomarkers, further experimental studies are required to qualify the clinical utility of miRNAs to reflect dynamic changes in bone formation and microstructure.

Less strict intervention thresholds for the FRAX and TBS-adjusted FRAX predict clinical fractures in osteopenic postmenopausal women with no prior fractures.

Little is known about the clinical relevance of treating post-menopausal women with no prior history of fragility fracture and bone mineral densities (BMD) within the osteopenic range. In recent years, in addition to BMD and FRAX fracture probability assessments, a surrogate measure of bone micro-architecture quality, called the trabecular bone score (TBS), has been proven to predict future fragility fractures independently of both BMD and the FRAX. In this retrospective analysis of a follow-up study, we compared three risk assessment instruments-the FRAX, the TBS, and a TBS-adjusted FRAX score-in their ability, to predict future fragility fractures over a minimum of five years of follow-up among post-menopausal osteopenic women with no prior fragility fractures. We also sought to determine if more- versus less-stringent criteria were better when stratifying patients into higher-risk patients warranting osteoporosis-targeted intervention versus lower-risk patients in whom intervention would usually be deemed unnecessary. Over a mean 5.2 years follow-up, 18 clinical fragility fractures were documented among 127 women in the age 50 years and older (mean age = 66.1). On multivariate analysis utilizing regression models and Kaplan-Meier curve analysis, less-stringent criteria for the FRAX and TBS-adjusted FRAX were capable of predicting future fractures (with sensitivity/specificity of 83/31; 39/77 and 78/50% for TBS, FRAX and TBS-adjusted FRAX, respectively), while more-stringent criteria were incapable of doing so (with sensitivity/specificity of 56/60; 39/77 and 39/74 for TBS, FRAX and TBS-adjusted FRAX, respectively). Neither TBS threshold alone was a significant predictor of future fracture in our study. However, hazard ratio analysis revealed slight superiority of the TBS-adjusted FRAX over the FRAX alone (HR = 3.09 vs. 2.79). Adjusting the FRAX tool by incorporating the TBS may be useful to optimize the detection of post-menopausal osteopenic women with no prior fractures who warrant osteoporosis-targeted therapy.

Long-Term Effects of Severe Burn Injury on Bone Turnover and Microarchitecture.

Severe burn injury triggers massive alterations in stress hormone levels with a dose-dependent hypermetabolic status including increased bone resorption. This study evaluated bone microarchitecture measured by noninvasive high-resolution peripheral quantitative computed tomography (HR-pQCT). Changes of serum bone turnover markers (BTM) as well as regulators of bone signaling pathways involved in skeletal health were assessed. Standardized effect sizes as a quantitative measure regarding the impact of serum changes and the prediction of these changes on bone microarchitecture were investigated. In total, 32 male patients with a severe burn injury (median total body surface area [TBSA], 40.5%; median age 40.5 years) and 28 matched male controls (median age 38.3 years) over a period of 24 months were included. In patients who had sustained a thermal injury, trabecular and cortical bone microstructure showed a continuous decline, whereas cortical porosity (Ct.Po) and pore volume increased. Initially, elevated levels of BTM and C-reactive protein (CRP) continuously decreased over time but remained elevated. In contrast, levels of soluble receptor activator of NF-κB ligand (sRANKL) increased over time. Osteocalcin, bone-specific alkaline phosphatase (BALP), intact N-terminal type 1 procollagen propeptide (P1NP), and cross-linked C-telopeptide (CTX) acutely reflected the increase of Ct.Po at the radius (R2 = 0.41), followed by the reduction of trabecular thickness at the tibia (R2 = 0.28). In adult male patients, early and sustained changes of markers of bone resorption, formation and regulators of bone signaling pathways, prolonged inflammatory cytokine activities in conjunction with muscle catabolism, and vitamin D insufficiency were observed. These alterations are directly linked to a prolonged deterioration of bone microstructure. The probably increased risk of fragility fractures should be of clinical concern and subject to future interventional studies with bone-protective agents. © 2017 American Society for Bone and Mineral Research.

Similarities in trabecular hypertrophy with site-specific differences in cortical morphology between men and women with type 2 diabetes mellitus.

The goal of our study was to investigate interactions between sex and type 2 diabetes mellitus (T2DM) with regard to morphology of the peripheral skeleton. We recruited 85 subjects (mean age, 57±11.4 years): women with and without T2DM (n = 17; n = 16); and men with and without T2DM (n = 26; n = 26). All patients underwent high-resolution, peripheral, quantitative, computed tomography (HR-pQCT) imaging of the ultradistal radius (UR) and tibia (UT). Local bone geometry, bone mineral density (BMD), and bone microarchitecture were obtained by quantitative analysis of HR-pQCT images. To reduce the amount of data and avoid multi-collinearity, we performed a factor-analysis of HR-pQCT parameters. Based on factor weight, trabecular BMD, trabecular number, cortical thickness, cortical BMD, and total area were chosen for post-hoc analyses. At the radius and tibia, diabetic men and women exhibited trabecular hypertrophy, with a significant positive main effect of T2DM on trabecular number. At the radius, cortical thickness was higher in diabetic subjects (+20.1%, p = 0.003). Interestingly, there was a statistical trend that suggested attenuation of tibial cortical hypertrophy in diabetic men (cortical thickness, pinteraction = 0.052). Moreover, we found an expected sexual dichotomy, with higher trabecular BMD, Tb.N, cortical BMD, Ct.Th, and total area in men than in women (p≤ 0.003) at both measurement sites. Our results suggest that skeletal hypertrophy associated with T2DM is present in men and women, but appears attenuated at the tibial cortex in men.