Long-Term Bone Mineral Density Changes in Kidney Transplant Recipients Treated with Denosumab: A Retrospective Study with Nonequivalent Control Group.

Data on the effectiveness of denosumab on osteoporosis after kidney transplantation are limited. We investigated the long-term bone mineral density (BMD) changes in kidney transplant recipients (KTRs) treated with denosumab compared to untreated KTRs. We enrolled KTRs treated with denosumab 60 mg/6 months for 4 years. An untreated group of sex and age-matched KTRs with a 1:1 ratio was included. The primary outcome was BMD changes assessed by Dual-energy X-ray Absorptiometry over 4 years. Data on serum creatinine, alkaline phosphatase (ALP), parathyroid hormone, and 25-hydroxyvitamin D were collected. All patients received oral cholecalciferol and calcium supplementation. 23 denosumab-treated KTRs were enrolled, and 23 untreated KTRs. The median time from transplant to the start of denosumab was 4 years (range 0:24). The denosumab group showed a significant increase from baseline in BMD at the lumbar spine (LS) (9.0 ± 10.7%, p < 0.001), and total hip (TH) (3.8 ± 7.9%, p = 0.041). The untreated group showed a significant decrease at all sites (- 3.0 ± 7%, p = 0.041 at the LS; - 6.3 ± 9.2%, p = 0.003 at the TH; - 6.7 ± 9.3%, p = 0.003 at the FN). The between-group differences in percent BMD changes were statistically significant at all sites. Similar results were found for the respective Z-scores. The ALP serum levels significantly decreased from baseline only in the denosumab group, with a significant between-group difference (p = 0.032). No significant differences in serum creatinine, hypocalcaemic events or acute graft rejection rates were observed. Four years of denosumab therapy were associated with increased BMD in KTRs, while untreated KTRs showed significant BMD losses at all sites.

Inhibition of de novo ceramide synthesis by Sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes.

BACKGROUND: Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular diseases (CVD). Dysregulated pro-apoptotic ceramide synthesis reduces ß-cell insulin secretion, thereby promoting hyperglycemic states which may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor cardiovascular outcomes. Sirtuin-1 (SIRT1) is a NAD + - dependent deacetylase that protects against pancreatic ß-cell dysfunction; however, systemic levels are decreased in obese T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice. METHODS AND RESULTS: Circulating SIRT1 levels were reduced in obese diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4-weeks prevented body weight gain, improved glucose tolerance, insulin sensitivity and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin-secretory function of ß-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in ß-cells thereby decreasing the rate limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among T2D patients, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored ß-cell function (HOMA2- ß) and were more likely to have T2D remission during follow-up. CONCLUSION: Acetylation of TLR4 promotes ß-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate cardiovascular complications of T2D.

The sequential antifracturative treatment: a meta-analysis of randomized clinical trials.

Background: Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term strategy should be scheduled by considering the mechanisms of action in therapy and the estimated fracture risk. Objective: A systematic review was conducted to evaluate the sequential strategy in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines. Design: Systematic review and meta-analysis. Data sources and methods: PubMed, Embase, and the Cochrane Library were investigated up to February 2021 to update the search of a recent systematic review. Randomized clinical trials (RCTs) that analyzed the sequential therapy of antiresorptive, anabolic treatment, or placebo in patients with or at risk of a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using fixed-effects models. The primary outcome was the risk of refracture, while the secondary outcome was the bone mineral density (BMD) change. Results: In all, 17 RCTs, ranging from low to high quality, met our inclusion criteria. A significantly reduced risk of fracture was detected at (i) 12 or 24 months after the switch from romosozumab to denosumab versus placebo to denosumab; (ii) 30 months from teriparatide to bisphosphonates versus placebo to bisphosphonates; and (iii) 12 months from romosozumab to alendronate versus the only alendronate therapy (specifically for vertebral fractures). In general, at 2 years after the switch from anabolic to antiresorptive drugs, a weighted BMD was increased at the lumbar spine, total hip, and femoral neck site. Conclusion: The Task Force formulated recommendations on sequential therapy, which is the first treatment with anabolic drugs or 'bone builders' in patients with very high or imminent risk of fracture.

A systematic review to evaluate the sequential therapy of antiresorptive (denosumab and bisphosphonate, such as alendronate, minodronate, risedronate, and etidronate), anabolic treatment (such as romosozumab, teriparatide), or placebo in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines Subjects with previous fragility fractures should promptly receive effective strategies to prevent the risk of subsequent events. Indeed, patients with a fragility fracture have a doubled risk of a new fracture. For this reason, it is essential to provide adequate sequential therapy based on the mechanisms and the rapidity of action. A systematic review was performed to identify the sequential strategy in patients at high- or imminent-risk of (re)fracture and to support the Panel of the Italian Fragility Fracture Guideline in formulating recommendations. Our systematic review included seventeen studies mostly focused on women and enabled us to strongly recommend the anabolic drugs as first-line treatment. Specifically, for the sequential therapy from anabolic to antiresorptive treatment, there was a significant reduction in the risk of different types of fractures after the switch from romosozumab to denosumab versus placebo to denosumab. These findings were confirmed at 24 months after the switch. Considering the sequential treatment from antiresorptive to anabolic medications, there was a decreased risk of fracture 12 months after the switch from placebo to teriparatide versus bisphosphonate or antiresorptive to teriparatide. Moreover, a greater bone mineral density increase after the switch from anabolic to antiresorptive medications was shown in the lumbar spine, total hip, and femoral neck. The results of this systematic review and meta-analysis confirm that initial treatment with anabolic drugs produces substantial bone mineral density improvements, and the transition to antiresorptive drugs can preserve or even amplify the acquired benefit. These findings support the choice to treat very high-risk individuals with anabolic drugs first, followed by antiresorptive drugs.

New point-of-care calcaneal ultrasound densitometer (Osteosys BeeTLE) compared to standard dual-energy X-ray absorptiometry (DXA).

Dual-energy X-ray absorptiometry (DXA) represents the gold standard for measuring bone mineral density (BMD). However, its size and bulkiness limit its use in mass screening. Portable and easily accessible instruments are more suitable for this purpose. We conducted a study to assess the repeatability, sensitivity, accuracy, and validation of a new ultrasound densitometer for the calcaneus (OsteoSys BeeTLe) compared to standard DXA. BMD (g/cm2) was measured at the femoral and lumbar spine levels using DXA (Discovery Acclaim (Hologic, Waltham, MA, USA) or Lunar Prodigy (GE Healthcare, Madison, WI, USA) devices). Bone Quality Index (BQI, a dimensionless measure of bone quality derived from measures of SOS [Speed Of Sound] and BUA [broadband ultrasound attenuation]) was measured with OsteoSys BeeTLe. The Bland-Altman test and simple linear regression were used to evaluate the association between values measured with the two instruments. Additionally, the ability of the T-score calculated with BeeTLe to identify patients with previous osteoporotic fractures was tested using ROC curves. A total of 201 patients (94.5% females) with a mean age of 62.1 ± 10.2 were included in the study. The BeeTLe instrument showed a coefficient of variation (CV, in 75 repeated measurements) of 1.21%, which was not statistically different from the CV of DXA (1.20%). We found a significant association between BQI and BMD at the femoral neck (r2 = 0.500, p < 0.0001), total femur (r2 = 0.545, p < 0.0001), and lumbar spine (r2 = 0.455, p < 0.0001). T-scores bias were 0.215 (SD 0.876), 0.021 (SD 0.889) and 0.523 (SD 0.092), for femoral neck, total hip and lumbar spine respectively. AUC for discriminating fracture and non-fractured patients were not significantly different with OsteoSys BeeTLe and standard DXA. In this preliminary study, BeeTLe, a new point-of-care ultrasound densitometer, demonstrated good repeatability and performance similar to DXA. Therefore, its use can be proposed in screening for osteoporosis.

Romosozumab added to ongoing denosumab in postmenopausal osteoporosis, a prospective observational study.

Background: Optimization of sequential and combination treatment is crucial in shaping long-term management of postmenopausal osteoporosis (OP). Methods: We conducted a 6-month prospective observational study on postmenopausal women with severe OP receiving treatment with romosozumab either alone (in patients naïve to treatment) or in combination with ongoing long-term denosumab (>2 years) or continuing ongoing denosumab alone (>2 years). We collected serum samples for bone turnover markers, bone modulators, and calcium phosphate metabolism at baseline, month 3 and month 6. BMD was assessed at baseline and after 6 months. Results: Fifty-two postmenopausal women with OP were included in the study. Nineteen received romosozumab alone, 11 received romosozumab combined to ongoing denosumab, and 22 continued denosumab alone. BMD increased significantly at all sites at 6 months of follow-up in the romosozumab alone group (femoral neck +8.1%, total hip +6.8%, and lumbar spine +7.9%). In contrast, BMD increased significantly only at lumbar spine in the combination group (+7.2%) and in the denosumab group (+1.5%). P1nP increased significantly in romosozumab groups at month 3 (+70.4% in romosozumab alone group and +99.1% in combination group). Sclerostin levels increased steeply in both romosozumab groups, and Dkk1 did not change. Conclusion: Romosozumab added to ongoing denosumab resulted in an increase in P1nP and lumbar spine BMD, but not in femoral neck BMD. For patients on denosumab, using romosozumab as an additional treatment appeared to be useful in terms of bone formation markers and spine BMD vs denosumab alone. Further randomized controlled trials, possibly powered to fracture outcomes, are needed to confirm our results.

Risk of fracture in women with glucocorticoid requiring diseases is independent from glucocorticoid use: An analysis on a nation-wide database.

OBJECTIVE: Glucocorticoid-induced osteoporosis (GIOP) is a common cause of secondary osteoporosis. However, glucocorticoid requiring diseases pose a risk themselves for fracture. The aim of the present study was to determine the risk of fracture associated with variety of glucocorticoid requiring diseases independently from glucocorticoid use and other risk factors for osteoporosis. METHODS: We conducted a retrospective cross-sectional analysis of a nation-wide cohort (DeFRACalc79 database). We used multivariable regression analysis adjusting for several risk factors for fracture and glucocorticoid intake to estimate the independent role of glucocorticoid requiring illnesses on fracture risk. RESULTS: We found that patients with rheumatoid arthritis, connective tissue diseases, chronic obstructive pulmonary disease (COPD) and neurological diseases were at greater risk of vertebral or hip fracture (crude ORs 1.31, 1.20, 1.92 and 2.97 respectively). After adjusting for potential confounders COPD and neurological diseases remained significantly associated with an increased risk of vertebral or hip fractures (aORs 1.33, 95 % CI 1.18-1.49 and 2.43, 95 % CI 2.17-2.74). Rheumatoid arthritis, COPD, IBD and neurological diseases also significantly increased the risk of non-vertebral, non-hip fractures (aORs 1.23, 1.42, 1.52 and 1.94 respectively). CONCLUSION: Some glucocorticoid requiring diseases were independently associated with an increased risk of fractures. COPD and neurological diseases with both vertebral and non-vertebral fracture risk while RA and IBD were independently associated only with non-vertebral, non-hip fractures.

Long-term effectiveness and predictors of bisphosphonate treatment in type I complex regional pain syndrome.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a painful disease that leads to chronic pain and disability. Bisphosphonates are largely used in the real-life for the treatment of CRPS, but data on long-term effectiveness and its predictors are lacking. METHODS: We conducted a longitudinal observational study on patients with type I CRPS treated with IV neridronate (100 mg on 4 occasions). Clinical and demographic characteristics were collected at baseline, after 3 months (M3) and after 12 months (M12). Multivariable logistic regression was employed to determine the factors associated with long-term response to treatment. RESULTS: 103 patients with type I CRPS treated with IV neridronate were included in the study. Mean VAS pain at baseline was 79.1 mm and decreased significantly at M3 (-45.9 mm, 95% CI 40.1 to 51.8) and M12 (-61.6 mm, 95% CI 55.3 to 67.9). Hyperalgesia and allodynia resolved in 84.3% and 88.1% of patients at M12. Loss of motion resolved in 53.5% of patients. The predictors of excellent response were gender (male better), predisposing event to CRPS (no event being better than any predisposing event), site of CRPS (lower limb being better), and early response at M3 on VAS pain (2.5 times the chance of being excellent responder every 10 mm decrease). CONCLUSIONS: In this real-life study neridronate was associated with rapid and progressive improvement of symptoms of CRPS which was maintained up to 3 years of follow-up. The predictors of excellent response were early response, lower limb localisation, absence of predisposing events and male gender.

Machine learning to characterize bone biomarkers profile in rheumatoid arthritis.

Background: Bone metabolism is disrupted in rheumatoid arthritis (RA); however, the bone metabolic signature of RA is poorly known. The objective of the study is to further characterize the bone metabolic profile of RA and compare it to psoriatic arthritis (PsA), systemic sclerosis (SSc) and healthy controls. Methods: We did a cross-sectional case-control study on consecutively enrolled patients and age-matched controls. We collected clinical characteristics, serum biomarkers related to bone metabolism and Bone Mineral Density (BMD). A multiple correlation analysis using Spearman's rank correlation coefficient was conducted within the RA patient group to investigate associations between biomarker levels and clinical variables. Machine learning (ML) models and Principal Component Analysis (PCA) was performed to evaluate the ability of bone biomarker profiles to differentiate RA patients from controls. Results: We found significantly lower BMD in RA patients compared to PsA, and Systemic Sclerosis SSc groups. RA patients exhibited higher Dkk1, sclerostin and lower P1nP and B-ALP levels compared to controls. No significant differences in CTX levels were noted. Correlation analysis revealed associations between bone biomarkers and clinical variables. PCA and ML highlighted distinct biomarker patterns in RA which can effectively discriminated bone biomarkers profile in RA from controls. Conclusion: Our study helped uncover the distinct bone profile in RA, including changes in bone density and unique biomarker patterns. These findings enhance our comprehension of the intricate links between inflammation, bone dynamics, and RA activity, offering potential insights for diagnostic and therapeutic advancements in managing bone involvement in this challenging condition.

Factors associated with radiographic progression in rheumatoid arthritis starting biological diseases modifying anti-rheumatic drugs (bDMARDs).

Background: Biological DMARDs (bDMARDs) have been proven to prevent joint damage and bone erosions. Nevertheless, approximately 15% of rheumatoid arthritis (RA) patients on bDMARDs will progress despite good control of joint inflammation. Objectives: The objective of our study is to investigate the factors associated with radiological progression of patients treated with bDMARDs. Design: We conducted a retrospective analysis of longitudinally collected data on RA patients starting bDMARDs. Methods: Presence or development of new erosions was assessed by a skilled rheumatologist at the time of the visit (baseline and 12 months thereafter). To determine the predictors of erosions, we employed multivariable logistic regression models. Discriminatory capacity for the prediction of new erosion development was assessed with receiver operating characteristic (ROC) curve, which was based on the logistic regression model. Results: A total of 578 RA patients starting bDMARDs were included in the study. Overall, 46 patients (approximately 10%) had radiographic progression (at least one new erosion) at 12 months of follow-up. The factors independently associated with higher risk of developing new erosions while on bDMARD were younger age, high disease activity at baseline, not being treated with cDMARDs, and presenting with erosions at baseline. In addition, we built a predictive model that can accurately foresee new erosions (AUC 0.846) in patients receiving bDMARDs. Conclusion: We found that baseline erosive disease, higher disease activity during treatment, younger age, and monotherapy were the factors independently associated with the development of bone erosions. Our study may inform future targeted intervention in RA patients at risk of radiographic progression.

Changes in bone turnover markers and bone modulators during abatacept treatment.

Rheumatoid arthritis (RA) causes bone loss, only partly related to inflammation. The impact of RA treatments on bone metabolism and their ability to mitigate bone loss remains uncertain. The primary goal of our study was to examine the influence of abatacept on serum levels of markers and regulators involved in bone turnover. Secondary objectives included evaluating changes in bone mineral density (BMD), bone health parameters, erosions, and exploring potential correlations among these parameters. We conducted a prospective observational study on patients with active seropositive RA failure to biological disease modifying anti-rheumatic drugs initiating treatment with abatacept. We measured at baseline and after 1, 2, 3, 6, 9 and 12 months: serum bone turnover markers (CTX, P1nP, B-ALP), bone modulators (Dkk-1, sclerostin, vitamin D, PTH, OPG and RANKL), BMD and radiographic parameters (modified Sharp van der Heijde score [mSvdH], bone health index [BHI] and metacarpal index [MCI]). Disease activity and glucocorticoid intake was monitored. 33 patients were enrolled in the study. We found a significant increase in markers of bone formation (B-ALP and P1nP) from baseline to M6 and M12. PTH increased significantly at M6 but not at M12. All other bone markers and modulators did not change. We found a significant decrease in BHI and MCI from baseline to M12 (median difference - 0.17 95% CI - 0.42 to - 0.10, p 0.001 and - 0.09 95% CI - 0.23 to - 0.07, respectively). BMD at femoral neck transitorily decreased at M6 (mean difference - 0.019 g/cm2 95% CI - 0.036 to - 0.001 p 0.04). BMD at total hip, lumbar spine and mSvdH score did not change significantly. P1nP delta at M12 correlated with delta mSvdH. Treatment with abatacept was associated with a significant increase in bone formation markers. The secondary and transient increase in PTH serum levels may be responsible of the transitory bone loss.

Medication holidays in osteoporosis: evidence-based recommendations from the Italian guidelines on 'Diagnosis, risk stratification, and continuity of care of fragility fractures' based on a systematic literature review.

Background: Noncommunicable, chronic diseases need pharmacological interventions for long periods or even throughout life. The temporary or permanent cessation of medication for a specific period, known as a 'medication holiday,' should be planned by healthcare professionals. Objectives: We evaluated the association between continuity (adherence or persistence) of treatment and several outcomes in patients with fragility fractures in the context of the development of the Italian Guidelines. Design: Systematic review. Data Sources and Methods: We systematically searched PubMed, Embase, and the Cochrane Library up to November 2020 for randomized clinical trials (RCTs) and observational studies that analyzed medication holidays in patients with fragility fracture. Three authors independently extracted data and appraised the risk of bias of the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Effect sizes were pooled in a meta-analysis using random effects models. Primary outcomes were refracture and quality of life; secondary outcomes were mortality and treatment-related adverse events. Results: Six RCTs and nine observational studies met our inclusion criteria, ranging from very low to moderate quality. The adherence to antiosteoporotic drugs was associated with a lower risk of nonvertebral fracture [relative risk (RR) 0.42, 95% confidence interval (CI) 0.20-0.87; three studies] than nonadherence, whereas no difference was detected in the health-related quality of life. A reduction in refracture risk was observed when continuous treatment was compared to discontinuous therapy (RR 0.49, 95% CI 0.25-0.98; three studies). A lower mortality rate was detected for the adherence and persistence measures, while no significant differences were noted in gastrointestinal side effects in individuals undergoing continuous versus discontinuous treatment. Conclusion: Our findings suggest that clinicians should promote adherence and persistence to antiosteoporotic treatment in patients with fragility fractures unless serious adverse effects occur.

Executive summary: Italian guidelines for diagnosis, risk stratification, and care continuity of fragility fractures 2021.

Background: Fragility fractures are a major public health concern owing to their worrying and growing burden and their onerous burden upon health systems. There is now a substantial body of evidence that individuals who have already suffered a fragility fracture are at a greater risk for further fractures, thus suggesting the potential for secondary prevention in this field. Purpose: This guideline aims to provide evidence-based recommendations for recognizing, stratifying the risk, treating, and managing patients with fragility fracture. This is a summary version of the full Italian guideline. Methods: The Italian Fragility Fracture Team appointed by the Italian National Health Institute was employed from January 2020 to February 2021 to (i) identify previously published systematic reviews and guidelines on the field, (ii) formulate relevant clinical questions, (iii) systematically review literature and summarize evidence, (iv) draft the Evidence to Decision Framework, and (v) formulate recommendations. Results: Overall, 351 original papers were included in our systematic review to answer six clinical questions. Recommendations were categorized into issues concerning (i) frailty recognition as the cause of bone fracture, (ii) (re)fracture risk assessment, for prioritizing interventions, and (iii) treatment and management of patients experiencing fragility fractures. Six recommendations were overall developed, of which one, four, and one were of high, moderate, and low quality, respectively. Conclusions: The current guidelines provide guidance to support individualized management of patients experiencing non-traumatic bone fracture to benefit from secondary prevention of (re)fracture. Although our recommendations are based on the best available evidence, questionable quality evidence is still available for some relevant clinical questions, so future research has the potential to reduce uncertainty about the effects of intervention and the reasons for doing so at a reasonable cost.

Chronic arthritides and bone structure: focus on rheumatoid arthritis-an update.

Normal bone remodeling depends of a balance between bone forming cells, osteoblasts and bone resorbing cells, the osteoclasts. In chronic arthritides and some inflammatory and autoimmune diseases such as rheumatoid arthritis, there is a great constellation of cytokines produced by pannus that impair bone formation and stimulate bone resorption by inducing osteoclast differentiation and inhibiting osteoblast maturation. Patients with chronic inflammation have multiple causes that lead to low bone mineral density, osteoporosis and a high risk of fracture including circulating cytokines, impaired mobility, chronic administration of glucocorticoids, low vitamin D levels and post-menopausal status in women, among others. Biologic agents and other therapeutic measures to reach prompt remission might ameliorate these deleterious effects. In many cases, bone acting agents need to be added to conventional treatment to reduce the risk of fractures and to preserve articular integrity and independency for daily living activities. A limited number of studies related to fractures in chronic arthritides were published, and future investigation is needed to determine the risk of fractures and the protective effects of different treatments to reduce this risk.

Bone Loss in Inflammatory Rheumatic Musculoskeletal Disease Patients Treated With Low-Dose Glucocorticoids and Prevention by Anti-Osteoporosis Medications.

OBJECTIVE: The negative effects of glucocorticoids on bone depend on dose and treatment duration. However, it is unclear whether a safe dose exists, especially for patients with inflammatory rheumatic musculoskeletal diseases (iRMDs). We undertook this study to determine the effects of glucocorticoid doses on bone health in iRMD patients. METHODS: We conducted a longitudinal cohort study on women with iRMD. Bone mineral density (BMD) and fractures were assessed prospectively and compared to a matched cohort without iRMD. Kaplan-Meier curves with log rank test were made for iRMD patients (stratified for glucocorticoid use and dose) and the matched cohort. Multivariable Cox regression survival models were also employed to analyze the effect of glucocorticoids on fracture. RESULTS: A total of 884 women with iRMD and 1,766 controls (matched for age, T score, and 10-year fracture risk) were included in the study and followed up for up to 6 years. BMD decreased significantly in all patients receiving glucocorticoids who were not receiving anti-osteoporosis treatment (-4.26% for ≥5 mg/day of prednisone equivalent, P = 0.0011; -4.23% for 2.5-5 mg/day, P = 0.0422; -2.66% for 0-2.5 mg/day, P = 0.0006). Anti-osteoporosis treatment (largely bisphosphonates) prevented bone loss only in patients receiving <5 mg/day of prednisone equivalent. Fracture incidence was higher in patients with iRMD compared to controls, but only glucocorticoid doses ≥5 mg/day were associated with significantly higher risk of fracture. CONCLUSION: Glucocorticoid doses as low as 2.5 mg/day were associated with BMD loss in iRMD patients, but this effect was preventable. BMD loss in patients receiving ≥5 mg/day was not totally prevented by anti-osteoporosis medications currently used in clinical practice, resulting in higher risk of fracture.

Association between short-term exposure to environmental air pollution and atopic dermatitis flare in patients treated with dupilumab.

Background: The magnitude of short/medium-term air pollution exposure on atopic dermatitis (AD) flare has not been fully investigated. The aim of the study was to investigate the association of short/medium-term exposure to airborne pollution on AD flares in patients treated with dupilumab. Methods: Observational case-crossover study. Patients with moderate-to-severe AD under treatment with dupilumab were included. The exposure of interest was the mean concentrations of coarse and fine particulate matter (PM10, PM2.5), nitrogen dioxide, and oxides (NO2, NOx). Different intervals were considered at 1 to 60 days before the AD flare and control visit, defined as the visit with the highest Eczema Area and Severity Index scores >8 and ≤7, respectively. A conditional logistic regression analysis adjusted for systemic treatments was employed to estimate the incremental odds (%) of flare every 10 µg/m3 pollutant concentration. Results: Data on 169 of 528 patients with AD having 1130 follow-up visits and 5840 air pollutant concentration measurements were retrieved. The mean age was 41.4 ± 20.3 years; 94 (55%) men. The incremental odds curve indicated a significant positive trend of AD flare for all pollutants in all time windows. At 60 days, every 10 µg/m3 PM10, PM2.5, NOx, and NO2 increase concentration was associated with 82%, 67%, 28%, and 113% odds of flare, respectively. Conclusions: In patients treated with dupilumab, acute air pollution exposure is associated with an increased risk for AD flare with a dose-response relationship.

Patients with osteoporosis: children of a lesser god.

Osteoporosis is a common non-communicable disease with enormous societal costs. Antiosteoporosis medications have been proven efficacious in reducing the refracture rate and mortality; moreover, we have now convincing evidence about the cost-effectiveness of antiosteoporotic medications. However, albeit preventable and treatable, osteoporosis has been somehow neglected by health authorities. Drugs approval has been unnecessarily lengthy, especially when compared with other non-communicable diseases. Herein, we discuss the issue of procrastinating drug approval in osteoporosis and future implications.

Fragility Score: a REMS-based indicator for the prediction of incident fragility fractures at 5 years.

BACKGROUND: Accurate estimation of the imminent fragility fracture risk currently represents a challenging task. The novel Fragility Score (FS) parameter, obtained during a Radiofrequency Echographic Multi Spectrometry (REMS) scan of lumbar or femoral regions, has been developed for the non-ionizing estimation of skeletal fragility. AIMS: The aim of this study was to assess the performance of FS in the early identification of patients at risk for incident fragility fractures with respect to bone mineral density (BMD) measurements. METHODS: Data from 1989 Caucasians of both genders were analysed and the incidence of fractures was assessed during a follow-up period up to 5 years. The diagnostic performance of FS to discriminate between patients with and without incident fragility fracture in comparison to that of the BMD T-scores measured by both Dual X-ray Absorptiometry (DXA) and REMS was assessed through ROC analysis. RESULTS: Concerning the prediction of generic osteoporotic fractures, FS provided AUC = 0.811 for women and AUC = 0.780 for men, which resulted in AUC = 0.715 and AUC = 0.758, respectively, when adjusted for age and body mass index (BMI). For the prediction of hip fractures, the corresponding values were AUC = 0.780 for women and AUC = 0.809 for men, which became AUC = 0.735 and AUC = 0.758, respectively, after age- and BMI-adjustment. Overall, FS showed the highest prediction ability for any considered fracture type in both genders, resulting always being significantly higher than either T-scores, whose AUC values were in the range 0.472-0.709. CONCLUSION: FS displayed a superior performance in fracture prediction, representing a valuable diagnostic tool to accurately detect a short-term fracture risk.

Tapering glucocorticoids and risk of flare in rheumatoid arthritis on biological disease-modifying antirheumatic drugs (bDMARDs).

INTRODUCTION: Glucocorticoids are still a mainstream of rheumatoid arthritis (RA) treatment. Reducing glucocorticoids should be attempted in all patients. However, choosing the right tapering strategy is challenging. The primary aim of our study is to determine the dose-response association between glucocorticoid tapering and risk of flare in RA. METHODS: We conducted a case-crossover study to determine the factors associated to higher risk of flare in patients with RA. In case-crossover studies time-varying factors are assessed before events (hazard periods) and before control periods. We defined hazard periods as the 6 months immediately preceding flares of RA. Control periods were the 6 months prior to visits without flare. Exposure of interest was the tapering of glucocorticoids to various doses. RESULTS: 508 patients with RA were included in the study and 267 (52.5%) had at least a flare and served as the case-crossover study population. 1545 visits were available for analysis and 345 (22.3%) flares were recorded. Discontinuation of glucocorticoids (ie, tapering to doses of 0 mg/day) and tapering to 0-2.5 mg/day was associated with higher risk of flare (adjusted OR (aOR) of 1.45, 95% CI: 1.13 to 2.24 and aOR of 1.37; 95% CI: 1.06 to 2.01, respectively). Tapering to doses >2.5 mg/day was not associated with significantly higher risk of flare. CONCLUSIONS: We found that tapering to doses of >2.5 mg/day was generally effective in terms of risk of flare. Flare risk was higher when glucocorticoids were tapered to doses ≤2.5 mg/day. Our study might help design new tapering strategies in patients with RA on biological disease-modifying antirheumatic drugs.