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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The effects of different cholecalciferol supplementation regimens on serum inflammatory cytokines in healthy subjects with vitamin D deficiency are still lacking. This is a single-center, open-label, randomized, parallel group study involving healthy subjects deficient in vitamin D (baseline 25OHD < 20 ng/mL) receiving oral cholecalciferol with three different dosing regimens: Group A: 10,000 IU/day for 8 weeks followed by 1000 IU/day for 4 weeks; Group B: 50,000 IU/week for 12 weeks and Group C: 100,000 IU every other week for 12 weeks. IL-17A, IL-6, IL-8, IL-10, IL-23 and TNFα were measured at baseline and at week 4, 8, 12, and 16. 75 healthy subjects were enrolled (58.7% female), with an average age of 34.1 ± 10.2 years. No statistical differences were observed among groups at baseline for either IL-6, IL-17A, IL-23, IL-8 or IL-10 at any time point; TNFα was indetectable. Concerning the whole sample, the time trend analysis showed a statistically significant linear trend for decreasing values over the treatment period for IL-6 (p = 0.016) and IL-17A (p = 0.006), while no significant time trends were observed for the other teste cytokines. No significant differences were found in the serum concentrations of the tested cytokines between week 12 and week 16. In young healthy individuals deficient in vitamin D, cholecalciferol administration showed a decrease in the serum IL-6 and IL-17A concentrations, without marked differences using the three regimens. [ABSTRACT FROM AUTHOR]

Patients living with osteoporosis are projected to increase dramatically in the next decade. Alongside the forecasted increased societal and economic burden, we will live a crisis of fractures. However, we will have novel pharmacological treatment to face this crisis and, more importantly, new optimized treatment strategies. Fracture liaison services will be probably implemented on a large scale worldwide, helping to prevent additional fractures in high-risk patients. In the next decade, novel advances in the diagnostic tools will be largely available. Moreover, new and more precise fracture risk assessment tools will change our ability to detect patients at high risk of fractures. Finally, big data and artificial intelligence will help us to move forward into the world of precision medicine. In the present review, we will discuss the future epidemiology and costs of osteoporosis, the advances in early and accurate diagnosis of osteoporosis, with a special focus on biomarkers and imaging tools. Then we will examine new and refined fracture risk assessment tools, the role of fracture liaison services, and a future perspective on osteoporosis treatment. [ABSTRACT FROM AUTHOR]

Background: There is increasing evidence that environmental air pollution is associated with the development of chronic inflammatory arthritides (CIA). The role of air pollutants on the biological treatment (biological disease‐modifying antirheumatic drugs [bDMARDs]) response of CIA is still unclear. Methods: We retrieved longitudinal data on patients affected by CIA on biological therapies and on the daily concentration of air pollutants in the Verona area. We designed a case‐crossover study to compare the exposure to pollutants in the 60‐day period preceding a drug switch or swap due to disease progression referent to the 60‐day period preceding a visit with stable treatment for at least 6 months. Results: A total of 1257 patients with CIA (863 with rheumatoid arthritis, 256 with psoriatic arthritis, and 138 with ankylosing spondylitis) with 5454 follow‐up visits were included in the study (median follow‐up 2.09 years [interquartile range: 0.82‐2.58 years]). A total of 282 patients were included in the case‐crossover study. We retrieved 13 636 daily air pollution records. We found that air pollutants' concentrations were higher in the 60‐day period before a failure of bDMARD response and prior to a switch or swap compared with the period preceding a visit with stable bDMARD therapy for at least 6 months. Conclusion: We found that environmental air pollution was a determinant of poor response to bDMARDs in a cohort of patients with CIA followed over a 5‐year period. An intervention aimed at decreasing fossil combustion emissions might have beneficial effects on biologic persistence rates of patients with CIA and economic expenditures related to switches and swaps. [ABSTRACT FROM AUTHOR]

Background: Central sensitization (CS) is a condition characterized by a disproportionate response to pain stimuli. We sought to investigate the prevalence of CS in patients with inflammatory arthritides and its association with measures of disease activity and functional disability. Methods: We conducted an observational retrospective study in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients. We administered to all the subjects in the study the CS inventory (CSI), a questionnaire that has been used for the diagnosis of CS. Demographic and clinical characteristics were collected as well as measures or disease activity [i.e. Simple Disease Activity Index, Disease Activity Score in PsA (DAPSA)] and functional disability [Health Assessment Questionnaire Disability Index (HAQ-DI)]. Patients with fibromyalgia were excluded from the analyses. The primary outcome measure was the presence of functional disability as assessed by HAQ-DI >1. Results: We enrolled 150 patients with inflammatory arthritides (78 PsA and 72 RA). Prevalence of CS was observed in 35.3% of the overall sample (29% in RA, 42.9% in PsA). Binary logistic regressions showed a strong, independent and linear association between functional disability and CS in both PsA and RA patients. The strength of this association was greater in PsA than in RA. Conclusion: CS is an important determinant of functional disability in patients with chronic inflammatory arthritides. PsA appeared to be more vulnerable to CS. In addition, in the presence of CS, DAPSA did not adequately capture the occurrence of functional disability. Therefore, special attention should be paid to PsA patients, in whom the concomitant diagnosis of CS should be routinely ruled out. [ABSTRACT FROM AUTHOR]

Objective. In this multicentre study, we aimed to evaluate the capacity of a computer-assisted automated QCT method to identify patients with SSc-associated interstitial lung disease (SSc-ILD) with high mortality risk according to validated composite clinical indexes (ILD-Gender, Age, Physiology index and du Bois index). Methods. Chest CT, anamnestic data and pulmonary function tests of 146 patients with SSc were retrospectively collected, and the ILD-Gender, Age, Physiology score and DuBois index were calculated. Each chest CT underwent an operator-independent quantitative assessment performed with a free medical image viewer (Horos). The correlation between clinical prediction models and QCT parameters was tested. A value of P<0.05 was considered statistically significant. Results. Most QCT parameters had a statistically different distribution in patients with diverging mortality risk according to both clinical prediction models (P<0.01). The cut-offs of QCT parameters were calculated by receiver operating characteristic curve analysis, and most of them could discriminate patients with different mortality risk according to clinical prediction models. Conclusion. QCT assessment of SSc-ILD can discriminate between well-defined different mortality risk categories, supporting its prognostic value. These findings, together with the operator independence, strengthen the validity and clinical usefulness of QCT for assessment of SSc-ILD. [ABSTRACT FROM AUTHOR]

Purpose. Interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary functional tests (PFTs) and semi-quantitative scores based on extent of ILD detectable on chest computed tomography (CT). CT quantitative indexes (QCTIs) are promising tools to assess extent of ILD. This study's aim is to evaluate the validity of QCTI compared with that of chest CT standard evaluation and PFTs. Moreover, QCTI differences between patients' subgroups according to prognostic stratifications were investigated. Methods. ILD-SSc of patients from six rheumatological clinics was routinely assessed with chest CT and PFTs. Patients were clustered according to prognosis based on functional and/or radiological examinations. Finally, chest CTs were processed with OsiriX in order to obtain QCTI. Results. Two hundred fifty-seven SSc patients were enrolled. QCTI correlation between extent of ILD and PFTs range from = 0.60 to 0.58 and from = 0.54 to 0.52, respectively. The majority of QCTI have a different distribution in patients' subgroups based on prognosis. Most of QCTI discriminate patients with an ILD severity leading to a poor prognosis. Conclusions. QCTI assessment of ILD-SSc is comparable to the evaluation based on chest CT and/or PFTs. QCTI values corresponding to severe ILD were identified. QCTIs are excellent candidates for a new and more reliable SSc-ILD assessment. [ABSTRACT FROM AUTHOR]

Comparative pharmacodynamic (PD) analyses on different dosing schedules for cholecalciferol supplementation are limited. This was an open-label, randomized, parallel-group study involving 75 healthy individuals deficient in vitamin D (baseline 25OHD < 20 ng/mL) receiving oral cholecalciferol with three different dosing regimens: Group A: 10,000 IU/day for 8 weeks followed by 1000 IU/day for 4 weeks; Group B: 50,000 IU/week for 12 weeks and Group C: 100,000 IU every other week for 12 weeks. Regulators of calcium and phosphate homeostasis, bone turnover markers and Wnt inhibitors were measured at baseline, Day 28, 53, 84, and 112. The 1,25OH2D increased at each time point. The increase was greater (p < 0.05) for group A vs. B and C at Day 28, and vs. group B at Day 56. No significant difference among groups was observed for the other biomarkers. The 24,25OH2D remained stable over time. PTH decreased at Day 84 and FGF-23 increased at all time points. CTX-I and PINP increased slightly at Day 28. BALP decreased from Day 56 onward. Dkk-1 increased from Day 56 onward, while sclerostin did not show significant changes. In healthy individuals deficient in vitamin D, vitamin D supplementation exerted effects on multiple regulators of calcium, phosphate and bone metabolism, without marked differences using the three regimens. [ABSTRACT FROM AUTHOR]

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.

Objective: Several pharmacological treatments have been proposed for the treatment of complex regional pain syndrome type-I (CRPS-I) in adults, but data regarding the efficacy of various agents for this disease is scarce. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to analyse the efficacy of the various pharmacological approaches in adults with CRPS-I., Methods: We systematically searched PubMed, Scopus, and Web of Science databases from the inception date to 30 June 2021 to identify placebo-controlled or active-controlled RCTs using bisphosphonates, ketamine, CSs, anti-epileptics, NSAIDs/COXIBs, opiates, antidepressants, scavengers/magnesium sulphate or IVIGs for the treatment of CRPS-I. The primary outcomes included changes in the visual analogue scale (VAS) or numeric rating scale (NRS) for pain before and after treatment., Results: We included 20 placebo-controlled or active-controlled RCTs (including a total of 818 adults with CRPS-I) that used bisphosphonates (n = 7), ketamine (n = 2), CSs (n = 2), anti-epileptics (n = 1), NSAIDs/selective inhibitors of cyclooxygenase-2 (COXIBs) (n = 2), scavengers/magnesium sulphate (n = 5), or IVIGs (n = 1) to treat CRPS-I during a median follow-up of 26 weeks. Treatment with bisphosphonates showed a significant reduction in the values of the VAS/NRS pain scale compared with placebo or reference therapy (random effects weighted mean difference [WMD]: -23.8, 95% CI: -28.0 to -19.6; I2 = 36.4%). Treatment with ketamine also documented a reduction in the values of the VAS/NRS for pain (random effects WMD: -8.27, 95% CI: -12.9 to -3.70; I2 = 0%). Treatment with other agents did not reduce the values of the VAS/NRS assessments of pain., Conclusion: This systematic review and meta-analysis supports the recommendation of parenteral bisphosphonates as the first-line agent in the treatment of CRPS-I., Trial Registration: Open Science Framework registries, https://osf.io/et9gu/, osf.io/et9gu., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Environmental air pollution has been associated with disruption of the immune system at a molecular level. The primary aim of the present study was to describe the association between long-term exposure to air pollution and risk of developing immune-mediated conditions., Methods: We conducted a retrospective observational study on a nationwide dataset of women and men. Diagnoses of various immune-mediated diseases (IMIDs) were retrieved. Data on the monitoring of particulate matter (PM)10 and PM2.5 concentrations were retrieved from the Italian Institute of Environmental Protection and Research. Generalised linear models were employed to determine the relationship between autoimmune diseases prevalence and PM., Results: 81 363 subjects were included in the study. We found a positive association between PM10 and the risk of autoimmune diseases (ρ+0.007, p 0.014). Every 10 µg/m 3 increase in PM10 concentration was associated with an incremental 7% risk of having autoimmune disease. Exposure to PM10 above 30 µg/m3 and PM2.5 above 20 µg/m 3 was associated with a 12% and 13% higher risk of autoimmune disease, respectively (adjusted OR (aOR) 1.12, 95% CI 1.05 to 1.20, and aOR 1.13, 95% CI 1.06 to 1.20). Exposure to PM10 was associated with an increased risk of rheumatoid arthritis; exposure to PM2.5 was associated with an increased risk of rheumatoid arthritis, connective tissue diseases (CTDs) and inflammatory bowel diseases (IBD)., Conclusion: Long-term exposure to air pollution was associated with higher risk of developing autoimmune diseases, in particular rheumatoid arthritis, CTDs and IBD. Chronic exposure to levels above the threshold for human protection was associated with a 10% higher risk of developing IMIDs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: In polymyalgia rheumatica (PMR), data on bone turnover markers (BTM), on Wnt inhibitors (Dkk-1, sclerostin) and their changes induced by glucocorticoids (GC) are lacking. The aims of our study were to compare the baseline levels of Wnt inhibitors and BTM in PMR patients with healthy controls (HC) and to study their changes over the first 4 weeks of GC treatment. Materials and Methods: We enrolled 17 treatment-naïve patients affected by PMR and 17 age and sex-matched healthy controls (HC) from retired hospital personnel. PMR patients were administered methylprednisolone 16 mg daily for 4 weeks. Blood samples were taken at baseline and at week 4 for the PMR group, a single sample was taken for HC. N-propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (CTX-I), sclerostin, Dkk-1, and C-reactive protein (CRP) were dosed. Results: At baseline, Dkk-1 was significantly higher in the PMR group as compared to HC ( p = 0.002) while PINP, CTX-I and sclerostin levels were comparable between PMR patients and HC, After 4 weeks of GC treatment we found in the PMR group a decrease of PINP (mean ± SD percentage decrement as compared to baseline -40 ± 18.6%, p < 0.001), CTX-I (-23.5 ± 41.3%, p = 0.032), Dkk-1 (-22.4 ± 39.6, p = 0.033), and sclerostin (-32.49 ± 20.47, p < 0.001) as compared to baseline levels. Conclusions: In treatment-naïve PMR, systemic inflammation is associated with a dysregulation of the Wnt system (increased Dkk-1). Within the 1st month, treatment with GC showed noteworthy effects on bone resorption, formation, and on Wnt pathway modulators., (Copyright © 2020 Fassio, Adami, Idolazzi, Giollo, Viapiana, Vantaggiato, Benini, Rossini, Dejaco and Gatti.)

Bone loss is the result of a negative unbalance between bone formation ad bone resorption. In the last years, the studies on the Wnt canonical pathway have highlighted its crucial role in bone balance through its influence on the activity and maturation of the osteoblast line and in the Receptor Activator of Nuclear Factor κ B (RANK) - RANK ligand (RANKL)/Osteoprotegerin (OPG) system. These mechanisms are involved not only in the pathological processes inducing not only systemic bone loss (i.e. Postmenopausal osteoporosis, glucocorticoid- induced osteoporosis, etc.), but also at a local level, as happens in Rheumatoid Arthritis (RA). Recently, several new drugs for the treatment of bone loss have been approved, while some others are still under development. The most promising new drugs in the treatment of osteoporosis include the antibody that neutralizes RANKL (denosumab, DMAb), monoclonal antibodies against sclerostin and parathyroid hormone-related protein analogue. Other new strategies for the prevention and treatment of bone loss include calcilytics, cathepsin K inhibitor or the combination or the sequential use of the current drugs. New insights concerning the treatment of the local bone loss in RA and in Complex Regional Pain Syndrome type I are also provided in this review., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)