Bone Turnover Markers and Wnt Signaling Modulators in Early Complex Regional Pain Syndrome. A Pre-specified Observational Study.

To explore serum levels of some bone turnover markers and the involvement of the Wnt signaling in CRPS-1. Query ID="Q1" Text="Please check and confirm whether the edit made to the article title is in order." We conducted an observational study on patients with early CRPS-1 recruited before any treatment. Clinical measures were assessed together with biochemical evaluation. Values of sclerostin, DKK1, CTX-I, and P1NP were compared with sex-age-matched healthy controls (HCs). We enrolled 34 patients diagnosed with CRPS-1 (mean age 59.3 ± 10.6 years, Male/Female 10/24), median disease duration = 2 weeks (IQR 1-5); median VAS score = 76 (IQR 68-80). Foot localization was slightly more frequent than hand localization (18/16). No statistically significant difference was found between CRPS-1 patients and HCs for CTX-I (0.3 ± 0.1 ng/ml vs 0.3 ± 0.1, p = 0.140), while mean serum values of P1NP were significantly higher in CRPS-1 patients compared to HCs (70.0 ± 38.8 ng/ml vs 50.1 ± 13.6, p = 0.005). Mean levels of sclerostin and DKK1 were lower in CRPS-1 patients vs HCs (sclerostin 28.4 ± 10.8 pmol/l vs 34.1 ± 11.6, p = 0.004; DKK1 12.9 ± 10.8 pmol/l vs 24.1 ± 11.9, p = 0.001). No statistically significant difference was found for all biochemical assessments in a subgroup of fracture-induced CRPS-1. No statistically significant differences were observed according to disease localization, disease duration, presence of hyperalgesia, allodynia, sudomotor alterations, and mild or moderate/severe swelling. No significant correlation emerged between sclerostin, DKK1 levels, baseline VAS score, or McGill Pain Questionnaire score. Bone involvement in early CRPS-1 does not seem to rely on increased osteoclast activity. Conversely, a serum marker of bone formation resulted increased. Both Sclerostin and DKK1 showed decreased values, probably suggesting a widespread osteocyte loss of function.Trial registration number: Eudract Number: 2014-001156-28.

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.

Environment and arthritis.

The present narrative review explores the multifactorial aetiology of rheumatoid arthritis (RA) and other immunemediated inflammatory disorders (IMIDs), emphasising the significant role of various environmental factors in disease development and exacerbation. Key modifiable environmental factors such as cigarette smoking and air pollution are identified as major contributors to RA. We will also focus on the influence of weather, seasonality, and particularly vitamin D levels, on RA activity, suggesting potential for seasonal management and supplementation to mitigate disease severity. The emerging role of diet and the gut microbiome in RA pathogenesis and progression is discussed as well, with dietary interventions and specific nutrients like omega-3 fatty acids offering protective benefits against inflammation. Despite the mounting evidence around these factors, further research is needed, to better understand the clinical impacts on RA, including well-designed randomised clinical trials.

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.

Radiofrequency echographic multi-spectrometry and DXA for the evaluation of bone mineral density in a peritoneal dialysis setting.

BACKGROUND: The aim of this real-life cross-sectional explorative study was to compare radiofrequency echographic multi-spectrometry (REMS) with dual-energy X-rays absorptiometry (DXA) in the BMD assessment of patients receiving peritoneal dialysis (PD). Furthermore, we investigated the relationship between lumbar aortic calcifications (AOCs) and the DXA lumbar measurements. METHODS: Consecutive patients referring to the PD clinic of our hospital were included. Lumbar spine and femur scans were acquired with both techniques (including lumbar laterolateral DXA scans). The risk assessment of two fracture risk algorithms (FRAX® and DeFRA®) were compared. Cohen's k coefficients were used to assess the inter-technique agreement in the classification of patients as osteoporotic. Lumbar AOCs were estimated semi-quantitatively on laterolateral DXA scans. RESULTS: 41 patients were enrolled. No significant differences were documented between the BMD T-scores measured through DXA or REMS at the femur. At the lumbar spine, the DXA anteroposterior mean T-score (- 0.49 ± 1.98) was significantly higher than both the laterolateral DXA (- 1.66 ± 0.99) and the REMS (- 2.00 ± 1.94) measurements (p < 0.01 vs both). No significant differences were found between the DXA and REMS fracture risk estimates with both algorithms. The inter-technique Cohen's k coefficient (for the worst T-score, any site) was 0.421, p < 0.001. The discrepancy between the DXA laterolateral and anteroposterior lumbar T-score was positively associated with the AOCs extent and severity (r = 0.402, p < 0.01). CONCLUSIONS: Our data showed a promising agreement, in a real-life PD setting, between DXA and REMS BMD assessment and in the consequent fracture risk estimation and confirm the AOCs interference on the diagnostic accuracy of lumbar DXA.

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.

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.

Pharmacological treatment in adult patients with CRPS-I: a systematic review and meta-analysis of randomized controlled trials.

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.

Association between environmental air pollution and rheumatoid arthritis flares.

OBJECTIVES: Environmental air pollution has been linked to the pathogenesis of RA. Nevertheless, evidence linking higher concentrations of air pollutants with the risk of RA reactivations is missing. The objective of the present study was to determine the association between RA flares and air pollution. METHODS: We collected longitudinal data of patients affected by RA and of the daily concentration of air pollutants in the Verona area. We designed a case-crossover study. We compared the exposure to pollutants in the 30-day and 60-day periods preceding an arthritic flare referent to the 30-day and 60-day preceding a low-disease activity visit. RESULTS: The study included 888 patients with RA with 3396 follow-up visits; 13 636 daily air pollution records were retrieved. We found an exposure-response relationship between the concentration of air pollutants and the risk of having abnormal CRP levels. Patients exposed to greater concentrations of air pollutants were at higher risk of having CRP levels ≥5 mg/l. Concentrations of CO, NO, NO2, NOx, PM10, PM2.5 and O3 were higher in the 60-day period preceding a flare. CONCLUSIONS: We found a striking association between air pollution and RA disease severity and reactivations in a cohort of patients followed over a 5-year period. The exposure to high levels of air pollutants was associated with increased CRP levels and a higher risk of experiencing a flare of arthritis. This excessive risk was evident at very low levels of exposure.

Diffuse Idiopathic Skeletal Hyperostosis (DISH) in Type 2 Diabetes: A New Imaging Possibility and a New Biomarker.

We performed a cross-sectional study to investigate the prevalence of Diffuse Idiopathic Skeletal Hyperostosis (DISH) through Dual-Energy X-ray absorptiometry (DXA) Vertebral Fracture Assessment (VFA) in a group of post-menopausal women with Type 2 Diabetes Mellitus (T2DM). We also explored several biomarkers of bone turnover metabolism, including Wnt pathway modulators. DXA-VFA was performed to detect the presence of DISH. Serum samples were collected from all patients at the time of study recruitment. 16 different serum biomarkers were tested between the two subgroups. Given the exploratory nature of the study, we did not adjust for multiplicity. At VFA analysis, among 96 individuals enrolled in the study 20 (20.8%) showed features of DISH. No statistically significant difference was found for BMD values, between the DISH and NO-DISH subgroups. Concerning blood biomarkers, DISH patients showed a significant difference only in the sclerostin serum levels (32 vs 35.5 pmol/L, for the DISH and NO-DISH subgroup, respectively; p = 0.010). After adjustment for confounding factors, sclerostin serum levels remained significantly lower in DISH group (p = 0.002). We demonstrated a non-negligible prevalence of DISH in a population of post-menopausal women affected by T2DM and suggested low serum sclerostin as a possible key feature associated with DISH presence. In addition, we propose DXA-VFA analysis, whose radiation dose is considerably lower than conventional radiography, as a viable diagnostic and prognostic mean to obtain data not only on bone health, but also for the screening for DISH in subjects at risk.

Acute Effects of Glucocorticoid Treatment, TNFα or IL-6R Blockade on Bone Turnover Markers and Wnt Inhibitors in Early Rheumatoid Arthritis: A Pilot Study.

Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-6 play a fundamental role in bone loss in rheumatoid arthritis (RA), partly due to the inhibition of the Wnt canonical pathway. The aim of our study was to investigate the short-term effects of three different treatments on Wnt inhibitors (Dkk-1 and sclerostin) and on bone turnover markers (BTMs): N-propeptide of type I collagen (PINP) and C-terminal telopeptide of type I collagen (ß-CTX-I). We performed a retrospective analysis of prospectively collected data. We enrolled women affected by early RA (< 12 months) with active disease (DAS28 ≥ 2.6) despite a 6-month treatment with methotrexate (10-15 mg/week), who then started certolizumab pegol, tocilizumab, or methyl-prednisolone (8 mg/daily). Patients were divided into three groups according to the treatment. Blood samples were collected at baseline, week 1, and week 4. We selected 14 patients treated with certolizumab pegol, 14 patients with tocilizumab, and 20 patients with methyl-prednisolone. No difference between any of the tested parameters was found at baseline. ß-CTX-I, Dkk-1, and sclerostin decreased after 1 week of treatment with certolizumab pegol (- 27% ± 21.5, - 50% ± 13.2, and - 30% ± 30.4, respectively, p < 0.05). Methyl-prednisolone induced similar changes, albeit less marked, on ß-CTX-I and Wnt inhibitors, with a decrease in PINP (- 16.1% ± 16.5, p < 0.05). Tocilizumab did not significantly affect BTMs or Wnt inhibitors. No significant changes were found for PTH and 25OHD. In the first four weeks of treatment, TNFα inhibition showed strong effects on BTMs and Wnt inhibitors, differently from IL-6 blockade. Glucocorticoids induced similar changes; nonetheless, they showed undesired effects on bone formation.

Glucocorticoid-induced osteoporosis update.

PURPOSE OF REVIEW: Steroid-induced osteoporosis or glucocorticoid-induced osteoporosis (GIOP) is a common form of secondary osteoporosis and is a cause of increased morbidity and mortality. The pathogenesis of GIOP includes decreased bone formation and increased bone resorption. Clinicians can rely on several effective medications for the treatment and prevention of GIOP, including antiresorptive drugs (i.e. bisphosphonates) and bone anabolic drugs (i.e. teriparatide). RECENT FINDINGS: Recent studies have further highlighted that GIOP is a major public health concern and have provided new insights on the pathogenesis of GIOP, in particular, the dose-dependent effects of glucocorticoids on bone. New evidence on the real-world effectiveness of established GIOP therapies have been recently published as well as the results of the 24-months denosumab randomized controlled trial in GIOP. SUMMARY: GIOP and fragility fractures are important adverse events related to the long-term use of glucocorticoids. Recent studies have provided additional data on the epidemiology and pathogenesis of GIOP and on the efficacy and effectiveness of GIOP therapies.

Effects of biological and targeted synthetic DMARDs on bone loss in rheumatoid arthritis.

Bone loss is a typical consequence of Rheumatoid Arthritis (RA). It occurs not only locally, affecting the inflamed joints (erosions), but also systemically, leading to osteopenia and/or overt osteoporosis, with increased risk of fragility fractures. This complication, often underestimated, can worsen the burden of disability in RA patients. Moreover, systemic and local bone loss are closely intertwined as osteoporosis per se can facilitate the development of erosions. A fundamental role in this process is played by the osteoimmunologic dysregulation typical of RA and other chronic inflammatory conditions. The poor response to the DMARDs, in terms of progression of bone erosions, might depend on the concomitant osteoporosis and on other determinants of bone loss. Thus, we need a deeper investigation in RA patients of bone health and effects of DMARDs on it and, eventually, a specific anti-osteoporotic treatment, other than DMARDs, for the prevention of both fragility fractures and bone erosions. The present review summarizes the most relevant evidence on systemic bone loss of biological and targeted synthetic DMARDs.

Secukinumab produces a quick increase in WNT signalling antagonists in patients with psoriatic arthritis.

OBJECTIVES: Interleukin-17 (IL-17) is an important cytokine involved in the pathogenesis of bone lesions of psoriatic arthritis (PsA). The aim of our study was to explore the short-term effects (≤6 months) of secukinumab (an anti-IL-17 antibody) on the serum levels of bone turnover markers (BTMs) and on the inhibitors of the WNT signalling pathway. METHODS: The study sample consisted of patients with PsA starting treatment with secukinumab 150 mg every month, and healthy controls (HCs). For the PsA group, the DAS28 score was recorded, and serum samples were collected at baseline, and then at Month 1, 3 and 6 of therapy. As for the HCs, a single observation was performed, with the relevant serum collection. Intact N-terminal propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (CTX-I-I), Dickkopf-related protein-1 (Dkk-1) and sclerostin were administered. RESULTS: 28 patients with PsA and 43 HCs were enrolled. Neither PINP nor CTX-I serum levels showed any significant variation during the observation period. Baseline mean Dkk-1 serum levels for the PsA arm were significantly lower than in the HC (p<0.05). Dkk-1 and sclerostin serum levels increased at Month 6 during the treatment with secukinumab (p<0.05 vs. baseline). When the PsA arm was compared to the HC, the difference between the serum levels of Dkk-1 lost significance at Month 6. CONCLUSIONS: Treatment with secukinumab does not have any significant short-term effect on BTMs, but may influence some fine regulators of the bone cell activity, such as the WNT inhibitors.

Osteoporosis Pathophysiology, Epidemiology, and Screening in Rheumatoid Arthritis.

PURPOSE OF REVIEW: To review the burden of osteoporosis (OP) in rheumatoid arthritis (RA) and to describe the OP screening strategies applied in RA. RECENT FINDINGS: RA is an inflammatory condition that predisposes patients to development of OP. OP in RA has a multifactorial pathogenesis with systemic inflammation and glucocorticoid use playing major roles. Newer studies have reported an intriguing association between RA autoantibodies and the development of OP. OP screening strategies in RA patients include clinical and vitamin D assessment, biochemical markers of bone remodeling, and bone imaging evaluations, particularly dual-energy X-ray absorptiometry (DXA). Fragility fractures are an important comorbidity of RA. OP screening strategies are both feasible and effective in RA patients and recommended by most specialty organizations. Given the considerable exposure to factors related to OP development, such as pro-inflammatory cytokines and glucocorticoid treatment, special attention should be directed to biochemical and DXA results in RA patients.

Pragmatic Clinical Trials in Osteoporosis.

PURPOSE OF REVIEW: In this review, we present the application of pragmatic clinical trials for evaluating interventions in osteoporosis, and we discuss methodological considerations for designing and conducting a pragmatic clinical trial compared with a classical randomized clinical trial. RECENT FINDINGS: Pragmatic clinical trials are a popular study design testing effectiveness of health interventions and are intended to address the limitations associated with traditional explanatory randomized clinical trials testing efficacy of interventions. To date, only few pragmatic clinical trials have been conducted in osteoporosis. Pragmatic clinical trials are conducted under routine clinical practice setting and are intended to inform policy makers and clinical decisions. Osteoporosis is a chronic disease well-suited to this particular study design given the existence of a clear and specific natural endpoint, namely fracture occurrence, and the availability of several treatments to prevent fractures.

Osteoporosis in Rheumatic Diseases.

Osteoporosis is a chronic disease characterized by an increased risk of fragility fracture. Patients affected by rheumatic diseases are at greater risk of developing osteoporosis. The purpose of the present review is to discuss the pathogenesis, epidemiology, and treatment of osteoporosis in patients affected by rheumatic diseases with special focus for rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, vasculitides, Sjogren syndrome, and crystal-induced arthritis.

The obesity paradox and osteoporosis.

Overweight and obesity according to the definition of the WHO are considered as an abnormal or excessive fat accumulation that may impair health. Studies comparing fracture incidence in obese and non-obese individuals have demonstrated that obesity, defined on the basis of body mass index (BMI), is associated with increased risk of fracture at some sites but seems to be protective at others. The results of the studies are influenced by the distribution of BMI in the population studied; for example, in cohorts with a low prevalence of obesity, a predilection for certain fracture sites in obese individuals becomes difficult to detect, whereas, in populations with a high prevalence of obesity, previously unreported associations may emerge. Furthermore, obesity can bring with itself many complications (Type 2 diabetes mellitus, vitamin D deficiency, and motor disability) which, in the long run, can have a definite influence in terms of overall risk and quality of life, as well. This is a narrative review focusing on the relationship between bone metabolism and overweight/obesity and dealing with the fundamental dilemma of a disease (obesity) apparently associated with improved values of bone mineral density, part of a complicated relationship which revolves around obesity called "the obesity paradox".

Correction to: The obesity paradox and osteoporosis.

Unfortunately, the author's first name and the family name were swapped and published in the original publication.