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 efficacy and safety of neridronate treatment in patients with complex regional pain syndrome type 1: a pre-specified, open-label, extension study.

Background: No data on the permanent and curative effect of bisphosphonate treatment in patients with complex regional pain syndrome type-1 (CRPS-1) are currently available. The aim of this pre-specified, open-label, observational study was to evaluate the long-term efficacy and safety of neridronate treatment. Design: A pre-specified, open-label, extension study. Methods: Patients treated with intramuscular (IM) placebo in the double-blind phase of the study were assigned to 100 mg intravenous (IV) neridronate treatment administered 4 times over 10 days. These patients, together with those previously treated with 400 mg IM neridronate, were followed for 1 year. Efficacy was assessed using a visual analogue scale (VAS) pain score. Changes in clinical signs and symptoms, quality of life (QoL) using the Short Form Health Survey (SF-36), and the McGill Pain Questionnaire were also assessed. Results: Benefits on pain, clinical and functional measures were maintained and further improved over 12 months in most patients treated with neridronate administered either IM or IV. In IM-treated patients, the percentage of those defined as responders (VAS score reduction ≥ 50%) progressively increased up to day 360 to 32 of 35 patients (91.4%). Among the 27 patients referred to as responders at the end of the double-blind phase, 26 reported the same result at day 360 (96.3%). In IV-treated patients, a responder rate of 88% (22 out 25) was found at day 360 (p = 0.66 between groups). Consistent improvements were also observed for all clinical signs and functional questionnaire. No drug-related adverse events were reported during the study. Conclusion: In patients with acute CRPS-1, the benefit in pain, clinical, and functional measures observed a few weeks after neridronate treatment administered either IM or IV is maintained and further improved over 12 months. Parenteral neridronate induces permanent disease remission preventing chronic pain and motor dysfunction. Trial registration: EU Clinical Trials Register (EudraCT Number): 2014-001156-28.

Persistence and recurrence in tumor-induced osteomalacia: A systematic review of the literature and results from a national survey/case series.

PURPOSE: Tumor induced osteomalacia (TIO) is a rare disease of mineral metabolism, whose clinical picture is dominated by hypophosphatemia usually due to an excess of circulating FGF23 produced by small mesenchymal tumors. Data on the real prevalence of the disease are lacking, with the knowledge of the disease mainly relying on case reports and small case series. No estimate is available on the prevalence of uncured TIO. METHODS: National multi-center, cross-sectional and retrospective study on persistent or recurrent cases of TIO followed in referral centers for bone diseases; systematic review of the published persistent and recurrent cases of TIO. Data from patients consecutively evaluated in referral Italian centers for bone diseases were collected; a PubMed search on persistent, recurrent and unoperable cases of TIO was carried out. RESULTS: Sixteen patients (mean age at diagnosis 52.5 ± 10.6 years) with persistent (n = 6, 37,5%), recurrent (n = 7, 43.7%) or not operable (n = 3, 18.8%) TIO were described. Delay in diagnosis (2.5 ± 1.3 years) was demonstrated. All patients experienced fragility fractures or pseudofractures and disabling bone and muscle pain. BMD was significantly reduced (mean T-score -2.7 ± 1.7 and -2.7 ± 0.9 at lumbar spine and femoral neck, respectively). Fourteen patients were maintained under therapy with phosphate salts and calcitriol, while in 2 patients therapy with burosumab, an anti-FGF23 antibody, was commenced. CONCLUSION: A significant number of patients with TIO remain either undiagnosed for tumor localization or tumor recur or persist after surgery. These patients with active disease represent possible candidates for burosumab treatment.

Intramuscular neridronate for the treatment of complex regional pain syndrome type 1: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling painful disease challenging to treat. This multicenter, randomized, double-blind placebo-controlled trial examined the efficacy of intramuscular (i.m.) neridronate in CRPS-1 patients. METHODS: A total of 78 patients diagnosed with CRPS-1 (aged 59.5 ± 10.3, 66.7% female) were randomly assigned to 25 mg (i.m.) neridronate (N = 41) given once daily for 16 consecutive days or placebo control (N = 37). Efficacy was assessed after 30 days using a visual analogue scale (VAS) pain score and the number of patients achieving ⩾50% reduction in VAS score. Change in clinical signs and symptoms, quality of life (QoL) using Short Form Health Survey (SF-36) and the McGill Pain Questionnaire were also assessed. RESULTS: After 30 days, VAS score decreased significantly to a greater extent in neridronate-treated patients versus placebo (31.9 ± 23.3 mm versus 52.3 ± 27.8 mm, p = 0.0003). Furthermore, the proportion of patients achieving a VAS reduction of ⩾50% was greater in the neridronate group (65.9% versus 29.7%, p = 0.0017). Clinical signs and symptoms were improved significantly in the neridronate group versus placebo for edema (72.5% versus 79.9%, p = 0.03), pain during motion (70% versus 83.3%, p = 0.0009), allodynia (20% versus 63.3%, p = 0.0004), and hyperalgesia (20% versus 56.7%, p = 0.0023). Whereas no difference was observed for QoL measures using the SF-36 questionnaire, three of the four pain variables using the McGill Pain Questionnaire improved significantly in the neridronate group. No serious drug-related adverse events were reported during the study. CONCLUSION: In patients with acute CRPS-1, i.m. injections of 25 mg neridronate were associated with clinically relevant benefit compared with placebo controls. TRIAL REGISTRATION: EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001156-28.

Determinants of Diagnostic Delay in Complex Regional Pain Syndrome Type 1: An Observational Study of 180 Consecutive New Cases.

BACKGROUND/OBJECTIVE: Complex regional pain syndrome type 1 (CRPS-1) is a disabling painful disease, with variable outcomes in terms of chronic pain and disability. A long time between onset and diagnosis seems predictive for late recovery and progression toward a chronic disease. This study aims to investigate demographic and clinical variables associated with delayed CRPS-1 diagnosis. METHODS: From March 2013 to January 2018, consecutive patients newly diagnosed according to International Association for the Study of Pain diagnostic criteria for CRPS-1 were recruited. Demographic and clinical variables were collected at diagnosis. Student t test and Mann-Whitney U test were used for comparisons; Cox proportional hazards model was applied to evaluate the variables associated with delayed CRPS-1 diagnosis. RESULTS: One hundred eighty patients entered the study. At diagnosis, women were older, and foot was more often involved than hand. The triggering event was more commonly a trauma without fracture for foot disease and a fracture for hand localization. No differences between hand and foot disease were found by the International Association for the Study of Pain diagnostic categories (clinical vs research) or pain measures. Variables significantly associated with a longer time between disease onset and diagnosis were foot localization, general practitioner referral, higher number of visits before CRPS diagnosis, and prior physiotherapy prescribed for symptoms later diagnosed as CRPS. An overt clinical manifestation (research CRPS-1) predicted a shorter delay. CONCLUSIONS: Foot localization, prior physiotherapy prescribed for symptoms later diagnosed as CRPS, and a disease without overt clinical manifestations were independent predictive factors for a delayed diagnosis. Clinicians should pay attention to these issues to ensure a timely diagnosis and possibly avoid progression toward a chronic disease.

Predictors of Responsiveness to Bisphosphonate Treatment in Patients with Complex Regional Pain Syndrome Type I: A Retrospective Chart Analysis.

Objective: The aim of this study was to assess whether the effectiveness of bisphosphonate infusion in patients with complex regional pain syndrome type I (CRPS-I) is influenced by variables related to patient and/or disease characteristics. Methods: This is a retrospective analysis of patients referred in the last five years to our rheumatologic tertiary care center, all fulfilling the Budapest CRPS-I diagnostic criteria and treated with three different bisphosphonate schedules (clodronate, pamidronate, and neridronate). For every subject, demographic and clinical variables were retrieved and retrospectively analyzed. We identified variables that independently influenced the therapeutic outcome of patients by a logistic regression analysis. For exploratory purposes, the effectiveness of the different bisphosphonate treatments employed was compared. Results: Among the 194 patients included in the analysis, the overall therapeutic response rate was 71.6%. Logistic regression analysis showed that the independent predictive variables for therapeutic effectiveness were disease duration (odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.72-0.96 for a one-month increment), fracture as a predisposing event (OR = 3.23, 95% CI = 1.29-8.03), and "warm" disease subtype (OR = 4.88, 95% CI = 1.57-15.20). These variables were found to influence the odds of responsiveness when analyzed together with age at onset, gender, and disease localization. No significant difference in therapeutic effectiveness was found by comparing the three different bisphosphonate schedules employed. Conclusion: Early disease, fracture as a predisposing event, and "warm" disease subtype are predictors of responsiveness to bisphosphonate treatment in patients with CRPS-I.

Algodystrophy: recent insight into the pathogenic framework.

Algodystrophy, nowadays called CRPS I, is a painful syndrome characterized by sensory and vasomotor disturbance, edema and functional impairment. Significant progress in knowledge about the pathogenic mechanisms of the disease have been recently achieved, but they are not yet fully understood and some clinical aspects are still lacking of a whole pathogenetic comprehension. The local release of pro-inflammatory neuropeptides and some cytokines may be the event that triggers and maintains the disease, causing hyperalgesia and allodynia. In the following phases, the impaired capillary permeability, the interstitial edema and the consequent hypoxia and local acidosis have been proposed as possible pathophysiological pathways. The local hyperactivity of the sympathetic nervous system supposed in the past has not be confirmed and the hypothesis of an altered nociceptive processing at CNS level has limited evidences in acute phases of the disease. The steady bone involvement could be confirmed by the efficacy of bisphosphonates in the treatment of early disease.

Intravenous neridronate in the treatment of acute painful knee osteoarthritis: a randomized controlled study.

OBJECTIVE: The aim of this randomized, double-blind, placebo-controlled study was to assess the efficacy of i.v. neridronate in controlling pain in patients with acute painful knee OA. METHODS: Sixty-four patients with acute knee pain (<3 months duration) suffering from knee OA with an MRI showing bone marrow lesions (BMLs) were randomized to receive either neridronate 100 mg given four times over 10 days or placebo. After 50 days the patients underwent clinical assessment and a further MRI was performed. Primary outcome was pain changes measured by a visual analogue scale (VAS; range 0-100). Secondary endpoints were WOMAC pain score, McGill pain questionnaire and 36-Item Short Form Health Survey. BMLs were evaluated by whole-organ MRI score. RESULTS: At the day of the last infusion the VAS decreased significantly more in the neridronate group [from 59.0 (s.d. 14.7) to 30.4 (s.d. 15.6); -48.4%; P < 0.001]. Fifty days later the VAS remained unchanged in the placebo group, while a further significant decrease was observed in the neridronate group [from 30.4 (s.d. 15.6) to 9.4 (s.d. 10.8); -69.1%; P < 0.001]. Significant improvements compared with the placebo group were found for most of the other indices of pain and quality of life. The BMLs score in the neridronate group showed significant decreases compared with basal values and those of the placebo-treated patients. Four months after the treatment, 72% of the placebo-treated patients resumed analgesic or anti-inflammatory drugs, but only 12.9% resumed treatment in the neridronate group. CONCLUSION: In patients with acute painful knee OA, four infusions of neridronate are associated with a clinically relevant pain benefit. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov), NCT01803360.

Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome for which no definite treatment has been established. The aim of this multi-centre, randomized, double-blind placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with CRP-I. METHODS: Eighty-two patients with CRP-I at either hand or foot were randomly assigned to i.v. infusion of 100 mg neridronate given four times over 10 days or placebo. After 50 days the former placebo patients were given open label the same regimen of neridronate. RESULTS: Within the first 20 days, visual analogue scale (VAS) score decreased significantly more in the neridronate group. In the following 20 days, VAS remained unchanged in the placebo group and further decreased in the active group by 46.5 mm (95% CI -52.5, -40.5) vs 22.6 mm (95% CI -28.8, -16.3) for placebo group (P < 0.0001). Significant improvements vs placebo were observed also for a number of other indices of pain and quality of life. During the open-extension phase in the formerly placebo group the results of treatment were superimposable on those seen during the blind phase in the active group. A year later none of the patients was referring symptoms linked to CRPS-I. CONCLUSION: In patients with acute CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits. These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I. TRIAL REGISTRATION: EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/, 2007-003372-18.

Initial studies to define the physiologic role of cN-II.

IMP preferring cytosolic 5'-nucleotidase II (cN-II) is a widespread enzyme whose amino acid sequence is highly conserved among vertebrates. Fluctuations of its activity have been reported in some pathological conditions and its mRNA levels have been proposed as a prognostic factor for poor outcome in patients with adult acute myeloid leukemia. As a member of the oxypurine cycle, cN-II is involved in the regulation of intracellular concentration of 5'-inosine monophosphate (IMP), 5'-guanosine monophosphate (GMP), and also 5-phosphoribose 1-pyrophosphate (PRPP) and is therefore involved in the regulation of purine and pyrimidine de novo and salvage synthesis. In addition, several studies demonstrated the involvement of cN-II in pro-drug metabolism. Notwithstanding some publications indicating that cN-II is essential for the survival of several cell types, its role in cell metabolism remains uncertain. To address this issue, we built two eucaryotic cellular models characterized by different cN-II expression levels: a constitutive cN-II knockdown in the astrocytoma cell line (ADF) by short hairpin RNA (shRNA) strategy and a cN-II expression in the diploid strain RS112 of Saccharomyces cerevisiae. Preliminary results suggest that cN-II is essential for cell viability, probably because it is directly involved in the regulation of nucleotide pools. These two experimental approaches could be very useful for the design of a personalized chemotherapy.

Demographic and clinical features related to a symptomatic onset of Paget's disease of bone.

OBJECTIVE: Paget's disease of bone (PDB) is a focal disorder of skeletal remodeling that can lead to bone pain, deformity, and fractures, but it can often be asymptomatic for a long time. This study investigated which factors may distinguish patients with clinical manifestations from asymptomatic patients. METHODS: The study group consisted of 224 patients with PDB referred to our Bone Disease Unit. For all patients, data were collected about clinical and demographic variables and diagnostic procedures. Logistic regression analyses were used to assess the role of recorded variables on the odds of being diagnosed clinically rather than by chance. RESULTS: Among the 124 patients with clinical manifestations leading to the diagnosis (55.4%), 36 subjects complained of bone pain, 32 articular pain, 42 back pain, 2 headache; 9 had fractures in Paget bone, and 3 had bone deformity. In 100 patients (44.6%) PDB was diagnosed by chance. At the multivariate analysis, only the number of bones involved (OR for 1 site increment = 1.18, 95% CI: 1.007-1.402; p = 0.04) acted as an independent predictor for a clinical diagnosis. Some skeletal localizations were associated with a clinical diagnosis: the involvement of lumbar spine (OR = 2.085, 95% CI: 1.024-4.224; p = 0.043) was more likely in symptomatic patients; pelvis and tibia showed a borderline statistical significance. The skull was predictive for asymptomatic PDB. CONCLUSION: A systematic laboratory screening including serum alkaline phosphatase of an older subject complaining of bone pain, articular pain, or back pain is the sole strategy to improve the diagnostic sensitivity for PDB.

Effects of dietary calcium intake on body weight and prevalence of osteoporosis in early postmenopausal women.

BACKGROUND: High calcium intakes seem to be ineffective at reducing bone loss in early postmenopausal women. However, the inverse relation between calcium intake and body weight can attenuate the negative effect of a low dietary calcium intake. OBJECTIVE: The objective was to assess the role of dietary calcium and body mass index (BMI) on osteoporosis, defined according to World Health Organization criteria as a lumbar bone density >2.5 SD below the T score. DESIGN: This was a cross-sectional, retrospective, observational study conducted in 1771 healthy, early postmenopausal women, who were not taking calcium supplements at the first densitometric evaluation. Weekly frequency of dairy food consumption was used to estimate the relative intake of dietary calcium. Total dairy intake was classified into 4 categories by quartile cutoffs. Multiple logistic regression analyses were used to study this sample. RESULTS: BMI and prevalence of overweight showed significant inverse trends with increasing dairy intake. Calcium intake was not associated with osteoporosis when overweight was not considered. However, when overweight was considered in the analysis, women with the lowest calcium intake were more likely to have osteoporosis (odds ratio: 1.46; 95% CI: 1.12, 1.89; P = 0.008) than were women with the highest calcium intake. CONCLUSIONS: In early postmenopausal women, a low dietary calcium intake may increase the risk of osteoporosis, but its negative effect can be offset by the greater BMI found in women with a low calcium intake.