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PURPOSE The aim of this study was to assess the accuracy and impact of different sizes and tube voltages on bone mineral density (BMD) assessment using a computed tomography (CT) topogram acquired with photon-counting detector CT in an osteopenic ex vivo animal spine. MATERIALS AND METHODS The lumbar back of a piglet was used to simulate osteopenia of the lumbar spine. Five fat layers (each with a thickness of 3 cm) were consecutively placed on top of the excised spine to emulate a total of 5 different sizes. Each size was repeatedly imaged on (A) a conventional dual-energy x-ray absorptiometry scanner as the reference standard, (B) a prototype photon-counting detector CT system at 120 kVp with energy thresholds at 20 and 70 keV, and (C) the same prototype system at 140 kVp with thresholds at 20 and 75 keV. Material-specific data were reconstructed from spectral topograms for B and C. Bone mineral density was measured for 3 lumbar vertebrae (L2-L4). A linear mixed-effects model was used to estimate the impact of vertebra, imaging setup, size, and their interaction term on BMD. RESULTS The BMD of the lumbar spine corresponded to a T score in humans between -4.2 and -4.8, which is seen in osteoporosis. Averaged across the 3 vertebrae and 5 sizes, mean BMD was 0.56 ± 0.03, 0.55 ± 0.02, and 0.55 ± 0.02 g/cm2 for setup A, B, and C, respectively. There was no significant influence of imaging setup (P = 0.7), simulated size (P = 0.67), and their interaction term (both P > 0.2) on BMD. Bone mineral density decreased significantly from L2 to L4 for all 3 setups (all P < 0.0001). Bone mineral density was 0.59 ± 0.01, 0.57 ± 0.01, and 0.52 ± 0.02 g/cm2 for L2, L3, and L4, respectively, for setup A; 0.57 ± 0.02, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup B; and 0.57 ± 0.01, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup C. CONCLUSION A single CT topogram acquired on photon-counting detector CT with 2 energy thresholds enabled BMD quantification with similar accuracy compared with dual-energy x-ray absorptiometry over a range of simulated sizes and tube voltages in an osteopenic ex vivo animal spine.

The present pilot study investigated the effect of Teriparatide 1–34 rh-PTH (TPT) in young women diagnosed with anorexia nervosa (AN), and markedly compromised Bone Mineral Density (BMD). Patients were included who had (i) very low BMD (defined as Z-Score T-Score Z-Score T-Score

Zusammenfassung. Bei chronisch entzündlichen Darmerkrankungen (Inflammatory Bowel Diseases, IBD) können nicht-entzündliche Gelenkschmerzen und entzündliche Gelenkmanifestationen auftreten. Letztere gehören zur Gruppe der Spondyloarthritiden. Sie werden am Achsenskelett als entzündlicher Rückenschmerz mit nächtlichen Schmerzen, Morgensteifigkeit und Besserung unter Aktivität manifest. Einschränkungen der Gelenkfunktion sind ebenfalls möglich. Bei anderen Patienten stehen periphere Gelenkbeschwerden im Vordergrund. Als Schmerzmedikamente werden COX-2-selektive, nicht-steroidale Antirheumatika (NSAR) empfohlen, da unselektive NSAR die zugrundeliegende IBD verschlimmern können. Am Achsenskelett werden Physiotherapie und Tumornekrosefaktor(TNF)-Inhibitoren eingesetzt, während bei peripherem Gelenkbefall Steroidinjektionen, Sulfasalazin und TNF-Inhibitoren wirksam sind. Entzündung, Malabsorption und Steroide führen bei IBD-Patienten zu Osteopenie und Osteoporose. Bei langdauernder Krankheitsaktivität bzw. langer Steroidgabe ist ein Screening mit DXA-Scan indiziert. Therapeutisch sollten ausreichend Kalzium und Vitamin D sowie gegebenenfalls Bisphosphonate gegeben werden.

Background: Studies in women with post-menopausal osteoporosis have shown that discontinuation of treatment with denosumab leads to an increased risk of vertebral fractures because of rebound bone turnover and rapid loss of bone mineral density (BMD). Methods: In a post hoc analysis of the Prolia for Osteoporosis of Transplant Operated Patient study, we analyzed the effect of denosumab withdrawal on BMD changes. Twenty-five de novo kidney transplant recipients (KTR) who were treated for 1 year with 2 six-monthly doses of denosumab on top of standard treatment (daily calcium and vitamin D) were compared to a control group of 29 KTR who received standard treatment alone. BMD changes were analyzed by repeated dual-energy X-ray absorptiometry shortly after transplantation (baseline), after 6 and 12 months (active treatment phase) and after 2–6.5 years (follow-up phase). Results: The average BMD at the lumbar spine declined markedly after discontinuation of treatment with denosumab but increased again thereafter. Thus, the average monthly change in lumbar spine BMD from month 12 onward was only 0.1 ± 2.8‰ in the denosumab group but 1.5 ± 1.9‰ in the control group (p = 0.021). The average monthly change in lumbar spine BMD from baseline to follow-up was similar in the control and denosumab group (1.1 ± 1.2‰ vs. 1.5 ± 2.4‰, p = 0.788). Similar results were seen at the total hip. Conclusions: In de novo KTR treated with 2 doses of denosumab, we detect a marked decrease in lumbar spine and hip BMD when denosumab is discontinued. Denosumab treatment should therefore not be discontinued without considering an alternative antiresorptive treatment.

Background: Metabolic acidosis (MA) is common in kidney transplant recipients (KTRs). Several studies have shown that MA is involved in the progression of chronic kidney disease. However, it is unclear if there is also a relationship between serum bicarbonate and graft function after kidney transplantation (KTx). We hypothesized that low serum bicarbonate is associated with a lower estimated glomerular filtration rate (eGFR) 1 year after KTx. Methods: We performed a post hoc analysis of a single-center, open-label randomized trial in 90 KTRs and investigated the relationship of serum bicarbonate and graft function in the first year after KTx. Results: Prevalence of MA was high after KTx (63%) and decreased to 28% after 1 year. Bicarbonate (20.6 ± 3.0 to 22.7 ± 2.7 mmol/L) increased in the first year after transplantation whereas eGFR (53.4 ± 15.8 to 56.9 ± 18.5 mL/min/1.73 m2) did not change significantly. Higher serum bicarbonate (p = 0.029) was associated with higher eGFR in the first year after KTx. Conclusion: Prevalence of MA is high in KTRs. In the first year after KTx, serum bicarbonate was positively correlated with eGFR, suggesting a potential role of MA in kidney graft function.

Background Bone mineral density (BMD) could be derived from CT localizer radiographs and could potentially enable opportunistic osteoporosis screening. Purpose To assess the accuracy and precision of BMD measurement using two localizer radiographs obtained with energy-integrating detector CT and a single localizer radiograph obtained with photon-counting detector CT. Materials and Methods A calibration phantom and a porcine phantom with lumbar vertebrae were imaged with a dual-energy x-ray absorptiometry (DXA) scanner, a clinical energy-integrating detector CT scanner, and a prototype photon-counting detector CT scanner. Two localizer radiographs at different combinations of tube voltages were obtained with energy-integrating detector CT, and one localizer radiograph was obtained with photon-counting detector CT using different energy thresholds. BMD was calculated for all three approaches and compared with the known specifications in the calibration phantom. In the animal phantom, BMDs from both CT systems were compared with those from the DXA scanner (the reference standard). Accuracy was defined as the measurement error of BMD (ΔBMD), and precision was defined as the coefficient of variation (in percentage). Radiation doses were estimated. Nonparametric tests were applied. Results In the calibration phantom, ΔBMD was smaller with both CT systems compared with the DXA scanner (both

Background: Low bone mineral density (BMD) represents a major risk factor for bone fractures in patients with chronic kidney disease (CKD) as well as after kidney transplantation. However, modalities to solidly predict patients at fracture risk are yet to be defined. Better understanding of bone turnover biomarkers (BTMs) may close this diagnostic gap. This study strives to correlate BTMs to BMD in kidney transplant recipients. Methods: Changes in BTMs – procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSAP), β-isomer of the C-terminal telopeptide of type I collagen, and urine deoxypyridinoline/Cr – at the time of transplant and 3 months were correlated to changes in BMD measured by dual-energy X-ray absorptiometry at the time of transplant, 6, and 12 months, respectively. Half of the collective was treated with denosumab twice yearly in addition to the standard treatment with calcium and vitamin D. Results: Changes in bone formation markers BSAP and P1NP within 3 months showed a significant negative correlation to changes in BMD at the hip within 6 months in denosumab-naïve patients. This correlation was abrogated by denosumab treatment. Conclusions: Changes in BSAP and P1NP showed promise in short-term prediction of BMD. We suggest further trials expanding on the knowledge of these BTMs with assessment of fracture risk, sequential measurements of BTMs within the first 6 months, and the additional use of computed tomography to assess BMD.

Overweight and obesity are multifactorial diseases caused by an imbalance in energy metabolism. An underlying genetic predisposition is often a factor in these conditions. In the cat breeding family of the Institute of Animal Nutrition at the Vetsuisse Faculty, University of Zurich, a segregating overweight phenotype with a genetic contribution was observed. From this breeding family, 26 kittens were followed from birth up to 8 months of age. During this time, food intake was measured using an automatic feeding station, and energy expenditure was investigated using indirect calorimetry at the ages of 4 and 6 months. Dual-energy X-ray absorptiometry (DEXA) was performed and blood glucose, leptin and insulin were measured at the ages of 4, 6 and 8 months. The kittens were also weighed daily for the first 2 weeks of life, every second day until weaning and once per week until 8 months of age. The body condition score (BCS) was evaluated monthly between 2 and 8 months of age. The main finding of this study is that a predisposition to overweight is connected to a higher food intake early in life, with no significant alterations in energy expenditure. The leptin blood levels were related to body fat percentage, and insulin sensitivity did not seem to be affected.

To develop age-, gender-, and regional-specific normative values for texture analysis (TA) of spinal computed tomography (CT) in subjects with normal bone mineral density (BMD), as defined by dual X-ray absorptiometry (DXA), and to determine age-, gender-, and regional-specific differences.In this retrospective, IRB-approved study, TA was performed on sagittal CT bone images of the thoracic and lumbar spine using dedicated software (MaZda) in 141 individuals with normal DXA BMD findings. Numbers of female and male subjects were balanced in each of six age decades. Three hundred and five TA features were analyzed in thoracic and lumbar vertebrae using free-hand regions-of-interest. Intraclass correlation (ICC) coefficients were calculated for determining intra- and inter-observer agreement of each feature. Further dimension reduction was performed with correlation analyses.The TA features with an ICC 0.81 indicating compromised intra- and inter-observer agreement and with Pearson correlation scores r 0.8 with other features were excluded from further analysis for dimension reduction. From the remaining 31 texture features, a significant correlation with age was found for the features mean (r = -0.489, p 0.001), variance (r = -0.681, p 0.001), kurtosis (r = 0.273, p 0.001), and WavEnLL_s4 (r = 0.273, p 0.001). Significant differences were found between genders for various higher-level texture features (p 0.001). Regional differences among the thoracic spine, thoracic-lumbar junction, and lumbar spine were found for most TA features (p 0.021).This study established normative values of TA features on CT images of the spine and showed age-, gender-, and regional-specific differences in individuals with normal BMD as defined by DXA.

Background The existence of a genetic predisposition to obesity is commonly recognized in humans and rodents. Recently, a link between genetics and overweight was shown in cats. The goal of this study was to identify the effect of diet composition on plasma levels of glucose, insulin, free fatty acids and triglycerides in cats receiving different diets (high-carbohydrate, high-fat and high-protein diets). Results Insulin and leptin concentrations were significantly correlated with phenotype. Insulin levels were lower, whereas leptin levels were higher in cats predisposed to overweight. The other blood parameters were not correlated with phenotype. Intake of the high-carbohydrate diet resulted in higher insulin concentrations compared with the two other diets. Insulin levels were within the values described for non-obese cats in previous studies. Conclusions There was no difference in metabolic response between the two groups. As the high-carbohydrate diet led to the highest insulin blood concentrations, it might be useful to avoid such diets in cats predisposed to overweight. In addition, even cats with genetically linked obesity can regain insulin sensitivity after weight loss.

Background There is an ongoing discussion about incorporating additional risk factors to established WHO fracture risk assessment tool (FRAX) to improve the prediction accuracy in clinical subgroups. We aimed to reach an expert consensus on possible additional predictive parameters for specific clinical subgroups. Methods Two-round modified Delphi survey: We generated a shortlist of experts from the authors’ lists of the pertinent literature and complemented the list with experts known to the authors. Participants were asked to name possible relevant risk factors besides the FRAX-parameters for the occurrence of osteoporotic fractures. Experts specified these possible predictors for specific subgroups of patients. In the second round the expert panel was asked to weight each parameter of every subgroup assigning a number between one (not important) to ten (very important). We defined the threshold for an expert consensus if the interquartile range (IQR) of a predictor was ≤2. The cut-off value of the median attributed weights for a relevant predictor was set at ≥7. Results Eleven experts of seven countries completed both rounds of the Delphi. The participants agreed on nine additional parameters for seven categories. For the category “secondary osteoporosis”, “older adults” and “nursing home patients”, there was a consensus that history of previous falls was relevant, while for men and postmenopausal women, there was a consensus that the spine fracture status was important. For the group “primary and secondary osteoporosis” the experts agreed on the parameters “high risk of falls”, “lumbar spine bone mineral density (BMD)” and “sarcopenia”. Conclusion This Delphi survey reached a consensus on various parameters that could be used to refine the currently existing FRAX for specific clinical situations or patient groups. The results may be useful for studies aiming at improving the predictive properties of instruments for fracture prediction.

From Axial Spondyloarthritis to Osteoporosis - Spectrum of Skeletal Involvement in Inflammatory Bowel Diseases

Life expectancy of people living with HIV (PLWH) is reaching similar length as in the general population. Accordingly, age-related comorbidities, including osteoporosis, are increasing. Fracture risk is higher and increases approximately 10 years earlier in PLWH. Classical risk factors of bone fragility are highly prevalent in PLWH but factors specific for HIV infection itself and the type of antiretroviral therapy (ART) (triple combination antiretroviral therapy) regimen (especially tenofovir and protease inhibitors) also contribute to bone loss. The majority of bone loss occurs during virus activity and at initiation of ART (immune reconstitution) and is associated with an increase of bone resorption (upregulation RANKL). Recent data indicate that calcium and vitamin D supplements as ART initiation lower BMD loss. The reduction of tenofovir plasma concentrations with tenofovir alafenamide attenuates BMD loss but it remains unknown whether it will contribute to reduce fracture risk. Hence, special considerations for the management of bone fragility in PLWH are warranted. Based on the current state of epidemiology and pathophysiology of osteoporosis in PLWH, we provide the consensus of the Swiss Association against Osteoporosis on best practice for diagnosis, prevention, and management of osteoporosis in this population. Periodic assessment of fracture risk is indicated in all HIV patients and general preventive measures should be implemented. All postmenopausal women, men above 50 years of age, and patients with other clinical risk for fragility fractures qualify for BMD measurement. An algorithm clarifies when treatment with bisphosphonates and review of ART regimen in favour of more bone-friendly options are indicated.

Implementation of AEC on the basis of the Moscow Power Engineering Institute is being solved. The paper considered the technical and economic conditions for the creation of AEC in the retail electricity (power) markets. Technological, organizational and economic systems of interaction between AEC participants formed on the grounds of the MPEI CHPP. To form a business model of AEC NRU MPEI functioning, an analysis of the energy consumption balance for consumers connected to the distribution networks of the MPEI CHPP was carried out as well as analysis of the technical and economic indicators of the MPEI CHPP operation. Through the research the possibilities of the AEC of NRU MPEI for payments to the unified energy system and economic efficiency of the AEC organization were assessed.

We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0.5% (95% CI -1.8% to 0.9%) in 44 patients in the control group (between-group difference 5.1% [95% CI 3.1-7.0%], p

Background/Aims: In a randomized controlled clinical trial in kidney transplant recipients (NCT01377467) we have recently shown that RANKL inhibition with denosumab significantly improved areal bone mineral density (aBMD) when given during the first year after transplantation. The effect of denosumab on skeletal microstructure and bone strength in kidney transplant recipients is not known. Methods: The purpose of the present bone microarchitecture ancillary study was to investigate high-resolution peripheral quantitative computed tomography (HRpQCT) data from the distal tibia and distal radius in 24 study patients that had been randomized to receive either two injections of denosumab 60 mg at baseline and after 6 months (n=10) or no treatment (n=14). Results: Consistent with the full trial findings, denosumab reduced biomarkers of bone turnover, and significantly increased aBMD at the lumbar spine (median difference of 4.7%; 95% confidence interval [CI] 2.6 - 7.8; pConclusions: These findings demonstrate that denosumab improves bone density and bone quality in first-year kidney transplant recipients at risk to develop osteoporosis.

Background Kidney transplant recipients (KTR) are at risk to lose bone mass. The trabecular bone score (TBS) represents a recently developed parameter of lumbar spine trabecular bone texture that correlates with the occurrence of fractures. Methods We analysed the 1-year changes in TBS in 44 de novo KTR that were randomized 1:1 to denosumab or no treatment. TBS was derived from dual energy X-ray absorptiometry and was correlated with 1-year areal bone mineral density (aBMD) changes at the lumbar spine and total hip. Correlations were also performed with parameters of peripheral bone microarchitecture and bone strength at the distal tibia and distal radius, as assessed by high-resolution peripheral quantitative computed tomography (HRpQCT) and micro-finite element analysis. Results The baseline TBS in KTR amounted to 1.312 ± 0.101, which is lower than the TBS of an age-matched normal control population (range 1.364–1.471). The TBS correlated positively with aBMD at the lumbar spine (Spearman’s ρ = 0.56; P Conclusions The TBS is a useful additional score of bone health, which may help to better define fracture risk. Treatment with denosumab led to improved trabecular bone texture in de novo KTR in addition to its beneficial effect on BMD.

This matched case–control study compared the rate of symptomatic adjacent-level vertebral compression fractures (VCF) within 1 year in patients operatively treated with kyphoplasty to a control group of non-operatively treated VCFs. The adjacent-level fracture rate did not show a significant difference between groups. To compare the rate of new symptomatic adjacent-level fractures within 1 year after an isolated osteoporotic vertebral compression fracture (VCF) treated by either kyphoplasty or non-operative treatment. Patients aged ≥ 50 years with an isolated, fresh, and symptomatic osteoporotic VCF who were treated by kyphoplasty were compared to patients of similar age, gender, vertebral segment, and bone mineral density who were treated non-operatively (n = 98). A matched case–control analysis was conducted by retrospective chart review, and the rate of new adjacent-level symptomatic vertebral fractures, defined as occurring within two segments of the index fracture, within the first year was determined. Ninety-eight patients (66 female, aged 73.5, SD 9.7 years) were analyzed in this matched case–control study. The adjacent fracture rate within 1 year was not different between the kyphoplasty group and the non-operative group (20.4 vs 18.4%; McNemar, p = 1.0). The time to a new adjacent fracture after the index fracture was significantly shorter in the kyphoplasty (7, SD 8 weeks) versus non-operative group (22, SD 13 weeks). Patients with osteoporotic VCFs treated with kyphoplasty did not show an increased rate of additional symptomatic adjacent-level VCFs when compared to a non-operative control group matched for age, gender, fracture level, and bone mineral density. Level of Evidence: Level III.

Antiosteoporotic drugs are recommended in patients with fragility fractures and in patients considered to be at high fracture risk on the basis of clinical risk factors and/or low bone mineral density. As first-line treatment most patients are started with an antiresorptive treatment, i.e. drugs that inhibit osteoclast development and/or function (bisphosphonates, denosumab, oestrogens or selective oestrogen receptor modulators). In the balance between benefits and risks of antiresorptive treatment, uncertainties remain regarding the optimal treatment duration and the management of patients after drug discontinuation. Based on the available evidence, this position statement will focus on the long-term management of osteoporosis therapy, formulating decision criteria for clinical practice.

Supplemental Digital Content is available in the text, Low bone mineral density (BMD) and osteoporosis remain frequent problems in patients with inflammatory bowel diseases (IBDs). Several guidelines with nonidentical recommendations exist and there is no general agreement regarding the optimal approach for osteoporosis screening in IBD patients. Clinical practice of osteoporosis screening and treatment remains insufficiently investigated. In the year 2014, a chart review of 877 patients included in the Swiss IBD Cohort study was performed to assess details of osteoporosis diagnostics and treatment. BMD measurements, osteoporosis treatment, and IBD medication were recorded. Our chart review revealed 253 dual-energy x-ray absorptiometry (DXA) scans in 877 IBD patients; osteoporosis was prevalent in 20% of tested patients. We identified widely differing osteoporosis screening rates among centers (11%–62%). A multivariate logistic regression analysis identified predictive factors for screening including steroid usage, long disease duration, and perianal disease; even after correction for all risk factors, the study center remained a strong independent predictor (odds ratio 2.3–21 compared to the center with the lowest screening rate). Treatment rates for patients with osteoporosis were suboptimal (55% for calcium, 65% for vitamin D) at the time of chart review. Similarly, a significant fraction of patients with current steroid medication were not treated with vitamin D or calcium (treatment rates 53% for calcium, 58% for vitamin D). For only 29% of patients with osteoporosis bisphosphonate treatment was started. Treatment rates also differed among centers, generally following screening rates. In patients with longitudinal DXA scans, calcium and vitamin D usage was significantly associated with improvement of BMD over time. Our analysis identified inconsistent usage of osteoporosis screening and underuse of osteoporosis treatment in IBD patients. Increasing awareness of osteoporosis as a significant clinical problem in IBD patients might improve patient care.

BACKGROUND: Infections are a major cause of morbidity and mortality in kidney allograft recipients. In this posthoc analysis of a randomized clinical trial which tested the effect of denosumab on bone mineral density we assessed the impact of this drug on the incidence and severity of infections in the first year after kidney transplantation. METHODS: In this clinical trial we randomized 90 de novo kidney transplant recipients shortly after transplantation to either denosumab on top of standard treatment (calcium and vitamin D) (n=46), or to standard treatment alone (n=44). Among all adverse events we analyzed all infections that occurred within the first year after transplantation, and compared their incidence and severity in both groups. RESULTS: Overall we identified more infections (n=146) in the denosumab group than in the control group (n=99). The most common infections were urinary tract infection (cystitis) (34.9% vs 25.2%), CMV viremia (17.8% vs 24.2%), flu-like syndrome (11.6% vs 14.1%), polyoma (BK) viremia (8.2% vs 11.1%), and herpes simplex infections (5.5% vs 4.0%). Episodes of urinary tract infection (cystitis) occurred more often in the denosumab than in the control group (51 vs 25 episodes in 24 vs 11 patients, p=0.008), whereas episodes of transplant pyelonephritis or urosepsis were not more frequent (3 vs 5 episodes). CONCLUSIONS: This post-hoc analysis reveals that treatment with denosumab to prevent bone loss in first-year kidney transplant recipients was associated with more frequent episodes of urinary tract infections, whereas other infections occurred with similar frequency in both treatment groups.

Background: Osteoarthritis is a common condition, typically treated with orally administered analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). Chronic administration of NSAIDs, serotoninnorepinephrine reuptake inhibitors (SNRIs, i.e., duloxetine), and opioid medications (i.e., tramadole) is regularly associated with multiple, serious side effects, in part due to the route of administration. Transdermal delivery of NSAIDs, such as ibuprofen, represents a potentially alternative treatment for this inflammatory pain condition with a better therapeutic profile. Objective: Investigate the safety and efficacy of a novel transdermal ibuprofen formulation (VALE®- ibuprofen) containing 10% ibuprofen, compared to a placebo in a randomized, double-blinded clinical trial, for clinical improvement in patients with moderate to severe painful osteoarthritis of the knee. Study Design: A randomized, placebo-controlled, double blind, multi-center Phase 2 clinical trial. Setting: An academic medical center, and private rheumatology and interventional pain management practices in Massachusetts and in Switzerland. Methods: The Phase 2 clinical study included patients with primary osteoarthritis in a single knee joint with a progression level of moderate to severe based in part on a grade II or III designation according to the Kellgren and Lawrence classification system. Patients received the corresponding, randomly assigned study formulation (VALE-ibuprofen or placebo) for application to the target knee at a dose of 2.0 grams of drug product (200 mg ibuprofen) twice daily for 14 days. The evaluation of the efficacy of the treatments utilized the widely accepted methods of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index and the Visual Analog Scale (VAS) scores for the patients. Results: The results indicate that the transdermal VALE-ibuprofen formulation was very well tolerated from a safety perspective during the 2-week trial and also produced significant, positive clinical improvements superior to the placebo in all clinical endpoints tested. In particular, the WOMACTotal and WOMACPhysical Functioning, for the VALE-ibuprofen, were superior compared to the placebo (P = 0.0283 and P = 0.0201, respectively). Other clinical endpoints including the WOMACPain, WOMACStiffness, and VASResting scores were superior to those obtained from the placebo group, trending towards statistical significance compared to placebo (P = 0.0811, 0.1103, and 0.0785, respectively). Based on the Patient and Physician Global Impression of Change survey, patient satisfaction slightly improved across both groups; however, no statistical significance was detectable as compared to the baseline. Limitations: The sample size of 64 subjects in the final data analysis and the lack of including an orally administered drug group are limitations of this study. Conclusions: The use of transdermal VALE-ibuprofen has beneficial clinical effects on the pain levels experienced in some patients with moderate to severe osteoarthritis of the knee as measured by the WOMAC Osteoarthritis Indices for stiffness, pain, physical function, and total. Visual Analog Scales (VAS) tests, VASMotion and VASWeight-bearing, again while appeared superior to placebo, were not statistically different from placebo. Clinical Trial Registration: NCT01496326 Key words: Ibuprofen, transdermal treatment, VALE-ibuprofen, knee osteoarthritis, Visual Analog Scale, WOMAC score

Low bone mineral density (BMD) remains a frequent problem in patients with inflammatory bowel diseases (IBD). There is no general agreement regarding osteoporosis screening in IBD patients.Cases of low BMD and disease characteristics were retrieved from 3172 patients of the Swiss IBD cohort study. Multivariate logistic regression analysis was conducted for predictive modeling. In a subgroup of 877 patients, 253 dual-energy X-ray absorptiometry (DXA) scans were available for validation.Low BMD was prevalent in 19% of patients. We identified seven predictive factors: type of IBD, age, recent steroid usage, low body mass index, perianal disease, recent high disease activity and malabsorption syndrome. Low BMD could be predicted with a sensitivity of 79% and a specificity of 64%, a positive predictive value (PPV) of 35% and a negative predictive value (NPV) of 93%. The area under the curve of the receiver operating characteristics was 0.78. In the validation cohort we calculated a PPV of 26% and an NPV of 88%.We provide a comprehensive analysis of risk factors for low BMD and propose a predictive model with seven clinical variables. The high NPV of models such as ours might help in excluding low BMD to prevent futile investigations.

Patients with asthma have an increased risk of Streptococcus pyogenes infection compared with those without asthma. It is unknown whether this is true for children with other atopic conditions such as atopic dermatitis or allergic rhinitis. To determine the risk of developing S. pyogenes infections of the upper respiratory tract in children and adolescents with atopic dermatitis and/or allergic rhinitis. We conducted a retrospective cohort study that followed a convenience sample of 340 healthy children. Atopic dermatitis or eczema and allergic rhinitis or hay fever were determined based on a physician diagnosis documented in medical records. All laboratory test results of cultures, rapid antigen detection, and polymerase chain reaction tests for S. pyogenes infections during the first 18 years of life were collected to compare the incidence of S. pyogenes infections between children with and without a physician diagnosis of atopic conditions. A Poisson regression was fit to determine the association between asthma and S. pyogenes infections, controlling for other covariates including asthma. Of the 340 subjects, 327 were eligible for the study. Of these 327 subjects, 143 (44%) had atopic conditions other than asthma. The incidence of S. pyogenes infections in children with atopic conditions other than asthma and those without atopic conditions was 0.24 per person-year and 0.18 per person-year, respectively. The adjusted risk ratios for allergic rhinitis and atopic dermatitis were 1.36 (95% CI 1.07 to 1.66, p=0.011) and 1.30 (95% CI 0.98 to 1.71, p=0.06), respectively, controlling for asthma and other covariates. In addition to asthma, allergic rhinitis but not atopic dermatitis is associated with an increased risk of S. pyogenes upper respiratory tract infections.

Background/Aims: Sclerostin is secreted by osteocytes. As a circulating inhibitor of the Wnt-signaling pathway it inhibits bone formation and contributes to the development of osteoporosis. Sclerostin levels are elevated in patients with chronic kidney disease and end-stage renal disease. Since data for patients after kidney transplantation are scarce, we have prospectively measured sclerostin levels before and during the first year after renal transplantation and have examined the association of sclerostin with parameters of bone mineral metabolism and with bone mineral density. Methods: Sclerostin levels were measured by ELISA in 42 consecutive renal transplant recipients before and at defined intervals in the first year after transplantation. Bone mineral density was measured by dual energy X-ray absorptiometry. Results: Pre-transplant serum sclerostin levels were elevated in all patients (61.8 ± 32.3 pmol/l, normal range 20-30 pmol/l). Within 15 days after transplantation and correlating with the improvement of renal function, sclerostin levels dropped to 21.0 ± 14.7 pmol/l and subsequently increased to 23.8 ± 14.9 and 28.0 ± 16.8 pmol/l after 6 and 12 months, respectively (PConclusions: The rapid reduction of elevated serum sclerostin levels shortly after kidney transplantation parallels the improvement of renal function, but contrasts with the more delayed improvement of hyperparathyroidism. The normalization of both hormones could contribute to improved bone health after renal transplantation.

Background Circumstantial evidence from preclinical studies indicates a key role of serotonin (5-HT) signaling via the 5-HT-2B receptor in the development of fibrosis. Terguride is an orally available 5-HT-2 receptor inhibitor that has shown beneficial effects in different animal models of systemic sclerosis (SSc). Objectives To evaluate the efficacy of Terguride for the treatment of fibrosis in patients with SSc in an investigator initiated phase 2 proof of concept study. Methods Main inclusion criteria were fulfillment of ACR classification criteria and diffuse cutaneous SSc (dcSSc). Patients with end-stage organ involvement and treatment with potentially disease modifying agents including immunosuppressives were excluded. Patients were treated with Terguride at up to 3 mg/d p.o. or standard of care (post hoc control) for three months. Primary efficacy endpoints were changes of pre-defined skin biopsy biomarkers over the three months treatment period. Secondary efficacy endpoints included change of mRSS and lung function parameters. Serious adverse events (SAEs) and AEs were coded using MedDRA. The study was externally monitored. Results Twelve patients were recruited into the Terguride group and 6 patients into the control group. The primary endpoints, skin biopsy biomarkers, showed a consistent and statistically significant down-regulation compared to the control group (Figure) for dermal thickness, myofibroblast counts and mRNA levels of col1a1, col1a2 as well as for the Lafyatis 4-gene biomarker set (COMP, THSP-1, SIGLEC-1, IFI-44). This was accompanied by a reduction in mRSS of - 32.3% versus baseline in the Terguride group versus stable values in the control group (p Conclusions Terguride was well tolerated in patients with dcSSc. Strong and consistent effects on fibrosis related skin biopsy biomarkers could be observed in this open-label controlled phase 2 proof of concept study, which was further supported by a significant improvement of the mRSS over the control group. These data justify further investigation in an upcoming randomized placebo controlled phase 3 study. Disclosure of Interest O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa, B. Maurer: None declared, S. Vettori: None declared, S. Blumhardt: None declared, D. Frey: None declared, A. Distler: None declared, C. Beyer: None declared, J. H. Distler Shareholder of: 4 D Science, Consultant for: Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma and Active Biotech

This study was designed to determine the relationship between asthma and the risk of developing Streptococcus pyogenes infections of the upper respiratory tract among children and adolescents. We conducted a retrospective cohort study that followed a convenience sample of 340 healthy children who participated in the Rochester Family Measles Study. Comprehensive medical record reviews determined asthma status by applying predetermined criteria. All laboratory test results of cultures, rapid antigen, and polymerase chain reaction tests for S. pyogenes infections during the first 18 years of life were collected to compare the incidence of S. pyogenes infections between asthmatic and nonasthmatic subjects. A Poisson regression was fit to determine the association between asthma and S. pyogenes infections controlling for other risk factors. Of the 340 subjects, we enrolled 327 who were eligible for this study. Of the 327 subjects, 114 (35%) had asthma. The incidences of S. pyogenes infections for asthmatic and nonasthmatic subjects were 0.25 per person-year and 0.18 per person-year, respectively. The adjusted risk ratio for asthma was 1.40 (95% CI, 1.12-1.74; p = 0.0029). Asthma in children is associated with an increased risk of S. pyogenes upper respiratory infections. The impact of asthma status on susceptibility to microbial infections needs to be considered in the context of a possible causal relationship between asthma and microbial infections. The mechanisms underlying this risk need to be elucidated.

This study assessed the ability of quantitative ultrasound (QUS) and digital X-ray radiogrammetry (DXR) to identify osteopenia and osteoporosis in patients with knee osteoarthritis (OA). One hundred and sixty-one patients with painful knee OA (81 men, 80 women; age 62.6+/-9.2 years, range 40-82 years) were included in this cross-sectional study and underwent dual-energy X-ray absorptiometry (DXA) of both hips and the lumbar spine, QUS of the phalanges and calcanei of both hands and heels, and DXR using radiographs of both hands. Unpaired t-test, Mann-Whitney U test, ROC analysis and Spearman's rank correlation were used for comparisons and correlation of methods. Using DXA as the reference standard, we defined a low bone mineral density (BMD) as a T-score < or =-1.0 at the lumbar spine or proximal femur. In contrast to phalangeal or calcaneal QUS, DXR was able to discriminate patients with a low BMD at the lumbar spine (p

Objective To determine whether chondroitin sulfate (CS) is effective in inhibiting cartilage loss in knee osteoarthritis (OA). Methods In this randomized, double-blind, placebo-controlled trial, 300 patients with knee OA were recruited from an outpatient clinic, from private practices, and through advertisements. Study patients were randomly assigned to receive either 800 mg CS or placebo once daily for 2 years. The primary outcome was joint space loss over 2 years as assessed by a posteroanterior radiograph of the knee in flexion; secondary outcomes included pain and function. Results Of 341 patients screened, 300 entered the study and were included in the intent-to-treat analysis. The 150 patients receiving placebo had progressive joint space narrowing, with a mean ± SD joint space loss of 0.14 ± 0.61 mm after 2 years (P = 0.001 compared with baseline). In contrast, there was no change in mean joint space width for the 150 patients receiving CS (0.00 ± 0.53 mm; P not significant compared with baseline). Similar results were found for minimum joint space narrowing. The differences in loss of joint space between the two groups were significant for mean joint space width (0.14 ± 0.57 mm; P = 0.04) and for minimum joint space width (0.12 ± 0.52 mm; P = 0.05). CS was well tolerated, with no significant differences in rates of adverse events between the two groups. Conclusion While there was no significant symptomatic effect in this study, long-term treatment with CS may retard radiographic progression in patients with OA of the knee. However, the clinical relevance of the observed structural results has to be further evaluated, and further studies are needed to confirm the structural effects of CS.

Based on the most recent studies, it clearly appears that long-term hormone replacement therapy (HRT) prevents fractures but does not improve established coronary artery disease. In addition, HRT leads to a small increase in breast cancer incidence and to a decrease in colorectal cancer incidence. HRT increases the incidence of venous thrombosis, pulmonary embolisms and strokes. As a consequence, HRT can no longer be recommended for primary or secondary prevention of cardiovascular diseases. In addition, it was also demonstrated that HRT was not able to improve cognitive functions and prevent dementia. Therefore regarding daily clinical practice, HRT certainly remains useful to control the symptoms of oestrogen deficiency in recently menopausal patients, but it should definitively no longer be recommended for long-term treatment.

To the Editor: Rheumatoid arthritis (RA) is the most common systemic connective tissue disease and affects 2.1 million people in the U.S., 1.5 million of whom are women ([1][1]). Patients with RA are at increased risk of developing premature cardiovascular disease, which shortens life expectancy by