CD14++ CD16- monocytes are the main source of 11ß-HSD type 1 after IL-4 stimulation.

The anti-inflammatory actions of IL-4 are well established through earlier findings. However, the exact mechanism it uses to downregulate the pro-inflammatory cytokine production through monocytes and macrophages is poorly understood. In this study, we examined the effect of IL-4 in the induction of 11ß-HSD1 in the two main classes of monocytes, CD14++ CD16- (CD14) and CD14+ CD16+ (CD16). Peripheral Blood Mononuclear Cells (PBMCs) were isolated from 17 healthy donors and were sorted into CD14 and CD16 subpopulations using cell sorting. Effect of IL-4 on 11ß-HSD1-enzyme activity was measured in sorted and unsorted monocytes using Homogeneous Time-Resolved Fluorescence (HTRF) and M1/M2 polarization analysis was performed by flow cytometry. Our results indicate that CD14 cells are the major source of 11ß-HSD1 enzyme after IL-4 stimulation and that M2 phenotype is not a pre-requisite for its synthesis.

Effects of TNF Inhibitors on Parathyroid Hormone and Wnt Signaling Antagonists in Rheumatoid Arthritis.

Tumor necrosis factor α inhibitors (TNFi) are the major class of biologic drug used for the treatment of Rheumatoid arthritis (RA). Their effects on inflammation and disease control are well established, but this is not true also for bone metabolism, especially for key factors as parathyroid hormone and Wnt pathway. Those two pathways are gaining importance in the pathogenesis RA bone damage, both systemic and local, but how the new treatment affects them is still largely unknown. We studied 54 RA patients who were starting an anti-TNFα treatment due to the failure of the conventional synthetic disease-modifying antirheumatic drugs. Serum levels of Wnt/ßcatenin pathway inhibitors (Dickkopf-related protein 1, Dkk1, and Sclerostin), Parathyroid hormone (PTH), vitamin D, and bone turnover markers were measured at baseline in the morning after fasting and after 6 months of therapy. We found a significant percentage increase in serum PTH (+32 ± 55 %; p = 0.002) and a decrease in Dkk1 mean serum levels (-2.9 ± 12.1; p = 0.05). PTH percentage changes were positively correlated both with C-terminal telopeptide of type I collagen and Dkk1 percentage changes. Sclerostin serum levels showed no significant difference. TNFi treatment provokes in the short term a rise in PTH levels and a decrease in Dkk1 serum levels. The increase of PTH might promote bone resorption and blunt the normalization of Dkk1 serum levels in RA. Those data give a new insight into TNFi metabolic effects on bone and suggest new strategies to achieve better results in terms of prevention of bone erosions and osteoporosis with TNFi treatment in RA.

Short-Term Effects of TNF Inhibitors on Bone Turnover Markers and Bone Mineral Density in Rheumatoid Arthritis.

TNFα inhibitors (TNFαI) exert positive effects on disease activity in rheumatoid arthritis (RA). Bone involvement is a major determinant of functional impairment in this disease. Here we investigated the short-term effects of TNFαI therapy on bone metabolism and density. We studied 54 patients with RA starting a TNFαI biologic drug, in whom any factor known to interfere with bone metabolism was excluded or rigorously accounted for. We measured at baseline and after 6-month therapy bone turnover markers: N-propeptide of type I collagen (P1NP), and bone alkaline phosphates for bone formation and serum C-terminal telopeptide of type I collagen (CTX) for bone resorption. We also evaluated bone mineral density (BMD) at hip and lumbar by dual-energy X-ray absorptiometry. All bone markers rose significantly and these changes were not dependent on steroid dosage. A significant decrease in femoral neck BMD was also observed. These results indicate that TNFαI therapy in RA over 6 months is associated with an early increase in bone turnover and a decline in hip BMD.

Safety issues and adverse reactions with osteoporosis management.

INTRODUCTION: Osteoporosis is a disease that has spread worldwide and has become a relevant public health problem. Over the last 2 decades, a number of drugs have been licensed for its treatment owing to their efficacy in preventing fragility fractures. The safety profiles of these drugs are well defined with data from extensive programs of pharmacovigilance to support it. AREAS COVERED: In this article we reviewed the long-term safety of Bisphosphonates, Calcium, Vitamin D, Selective Estrogen Receptor Modulators, Teriparatide and Denosumab. We excluded hormone replacement therapy that lost its indication for the treatment of osteoporosis. The license for the treatment of osteoporosis of Calcitonin was recently withdrawn and that of Strontium ranelate was severely limited. For both drugs, we report EMA statements about their safety profile. EXPERT OPINION: The safety profile of most available drugs for the treatment of osteoporosis is well defined and the most serious adverse events are either rare or predictable. Osteoporosis treatment is a favorable choice in patients at moderate-high risk of fracture, while in patients at low risk pharmacological prevention should involve consideration of the balance between the beneficial effects of treatment, the probability of adverse effects and costs.

Focal bone involvement in inflammatory arthritis: the role of IL17.

Conditions such as rheumatoid arthritis (RA) and spondyloarthritis (SpA, such as psoriatic arthritis, PsA, and ankylosing spondylitis, AS) are characterized by an imbalance between osteoclast (OC) bone resorption and osteoblast (OB) bone formation. The two conditions present substantial differences in bone involvement, which is probably related to the different expression of IL17 and TNFα, two cytokines that strongly promote osteoclastogenesis and focal bone erosions. TNFα is the major inflammatory cytokine in RA. It acts by both triggering OC bone erosion via the RANK-RANKL system, and suppressing OB bone formation through the overexpression of DKK1, a powerful inhibitor of the WNT bone anabolic signaling pathway. Differing from TNFα, IL17 promotes also osteogenesis, particularly at inflamed sites undergoing mechanical stress, such as entheses. Therefore, in RA, where overexpression of TNFα is higher than IL17, OC bone resorption largely prevails upon bone formation. In PsA and AS, the prevailing inflammatory cytokine is IL17, which promotes also osteogenesis. Given the prevalent involvement of entheses poor of OC, excess bone formation may even prevail over excess bone resorption. The results of clinical trials support the different pathophysiology of bone involvement in chronic arthritis. Inflammation control through anti-TNFα agents has not resulted in incomparable effects on radiographic progression and excess bone formation in both AS and PsA. Clinical trials investigating IL17 inhibitors, such as secukinumab, in patients with psoriatic disease are underway. The preliminary results on inflammation and symptoms appear positive, while long-term studies are required to demonstrate an effect on excess bone formation.

Dickkopf-1 and sclerostin serum levels in patients with systemic mastocytosis.

Bone involvement, mainly osteoporosis but also osteosclerosis, is frequent in patients with indolent systemic mastocytosis (ISM). The recent characterization of the canonical Wnt/ß-catenin pathway in the regulation of bone remodeling provided important insights for our understanding of the pathophysiology of a number of conditions. The regulation of Wnt pathway in bone is predominantly driven by the production of receptor inhibitors such as Dickkopf-1 (DKK1) and sclerostin (SOST). This study aimed to explore if the various bone involvements in patients with ISM might be explained by variations in serum levels of DKK1 and SOST. This is a cross-sectional study in an adult ISM cohort (13 men and 13 women with diagnosed ISM) and fifty-two healthy sex and age-matched controls. Early morning, fasting and venous sampling was obtained in all subjects. The main outcome measures were serum bone-specific alkaline phosphatase (bALP), C-terminal telopeptides of type I collagene (CTX), DKK1, SOST, parathyroid hormone (PTH), bone mineral density, and prevalent vertebral fractures. Mean DKK1 serum levels were about two-folds higher in patients, than in controls (65,0 ± 43.3 vs. 33.1 ± 19.4 pmol/L, respectively; p < 0.001), irrespective of the presence of osteoporotic or diffuse osteosclerotic bone involvement. DKK1 serum levels were positively correlated with PTH and both CTX and bALP. Mean SOST serum levels were not significantly different in patients versus controls, and we did not observe any significant correlation between SOST and any available clinical or laboratory parameters, with the only exception of a positive correlation with age. In conclusion, in our study, we observed that DKK1, but not SOST, serum levels significantly increased in ISM patients with various bone involvements, and correlated with PTH and bone turnover markers. Our results suggest that the Wnt/ß-catenin pathway is not primarily involved in the pathophysiology of the array of bone involvement in ISM.

Cost-effectiveness analysis of two rituximab retreatment regimens for longstanding rheumatoid arthritis.

OBJECTIVE: Rituximab (RTX) is licensed for second-line treatment of rheumatoid arthritis (RA) after first tumor necrosis factor (TNF) inhibitor failure. RTX is generally administered intravenously at 1 gm 2 weeks apart, and the retreatment is scheduled at the time of clinical relapse (regimen 1). A more intensive regimen is proposed with a fixed full cycle after 6 months (regimen 2) if remission is not reached. A cost-effectiveness analysis (CEA) compared these 2 regimens of RTX administration in patients with longstanding RA based on data provided by an observational study. METHODS: An observational retrospective study was conducted on 102 patients, enrolled in 3 hospitals and followed for ≥12 months. Forty-seven patients followed regimen 1, while 55 patients followed regimen 2. A CEA based on a Markov model was conducted. A lifelong and social perspective was adopted. CEA was conducted for the entire cohort and for the 2 subgroups separately (patients with positive rheumatoid factor and/or anti-cyclic citrullinated peptide and failures to TNF inhibitors). RESULTS: Results for the overall sample show at 10, 20, and 30 years that regimen 1 is less costly and associated with a higher quality of life compared to regimen 2. Probabilistic sensitivity analysis at 10 years estimated a probability of 95.1% for regimen 1 to be cost effective given a willingness to pay of €35,000/quality-adjusted life year, while for seropositive patients and for TNF failures it was estimated to be 92% and 92.7%, respectively. CONCLUSION: In longstanding RA, cost effectiveness of RTX retreatment at clinical relapse was found to be at least equivalent to the more intensive regimen proposed.

In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density.

OBJECTIVES: The objective of this study is to compare the serum levels of Dickkopf-1 (DKK1), a natural inhibitor of Wnt signalling, with parathyroid hormone (PTH) and bone involvement in patients with rheumatoid arthritis (RA). METHODS: This cross-sectional study includes 154 postmenopausal women with RA and 125 healthy controls. DKK1, 25OH vitamin D (25OHD), bone turnover markers, and PTH serum levels were measured by ELISA; lumbar spine and hip bone mineral density (BMD) and the erosion score were obtained. RESULTS: The RA patients and healthy controls were not significantly different in terms of age, body mass index, and 25OHD serum levels. The mean level of DKK1 and PTH were significantly higher in patients with RA than in healthy controls (172±68 [SD] vs. 96±55 pmoL/L, and 30±15 vs 22±11, respectively; p<0.0001). DKK1 serum levels were positively correlated with age (p<0.05) only in the healthy controls, while they were correlated with PTH serum levels only in the RA patients (p<0.0001). Among the RA patients, DKK1 levels adjusted for age, PTH and disease duration were significantly higher in patients with bone erosions (176 vs. 167 pmoL/L, respectively; p<0.05). DKK1 levels adjusted for age and PTH were negatively correlated with total hip BMD (p<0.05). In the RA patients not on treatment with bisphosphonates, DKK1 serum levels positively correlated with C-terminal telopeptides of type I collagene serum levels (p<0.05). CONCLUSIONS: In patients with RA, serum levels of DKK1 are significantly increased, correlate with PTH and are associated with increased risk of bone erosions and osteoporosis. However, this finding deserves confirmation in a larger and more selected population.

Bisphosphonates in Complex Regional Pain syndrome type I: how do they work?

Complex Regional Pain syndrome type I (CRPS-I) is a disease characterised by extreme pain for which no gold-standard treatment exists to date. In recent years a possible role for bisphosphonates in the treatment of CRPS-I has been proposed. These drugs were first used for their effect in decreasing pain in bone diseases in which bisphosphonates act through their antiosteoclastic properties (metastatic disease, Paget disease, myeloma). In CRPS-I, enhanced osteoclastic activity has never clearly been demonstrated and the benefit shown is possibly exerted by different mechanisms of action. In this paper we review other conjectural mechanisms involved in reducing pain intensity and improving clinical signs and functional status in these patients. The results of most studies on this topic show that bisphosphonates may be effective in the early phases of the disease, when scintigraphic bone scan more frequently shows a local radiotracer accumulation that possibly means a high local concentration of the drug. These features probably represent the required conditions by which bisphosphonates might modulate various inflammatory mediators that are upregulated in CRPS-I. Patients in whom a scintiscan is often negative (long-standing disease or a primarily cold disease) could be less responsive to this treatment. With these limitations, bisphosphonates appear to present a therapeutic strategy that has been proven to reliably offer benefits in patients with CRPS-I.

Zoledronic acid in osteoporosis secondary to mastocytosis.

BACKGROUND: Osteoporosis is the prevalent manifestation of bone involvement in patients with systemic mastocytosis. Mastocytosis-related osteoporosis is characterized by both absolute and relative prevalence of osteoclastic activity, consistent with the positive results reported in small series of patients with antiresorptive drugs, such as bisphosphonates. The aim of this study is to investigate the efficacy of zoledronic acid in patients with mastocytosis-related osteoporosis. METHODS: Twenty-five patients with osteoporosis secondary to indolent systemic mastocytosis were given a single intravenous infusion of 5 mg zoledronic acid dissolved in 100 mL of 0.9% saline over 60 minutes. RESULTS: After 1 year, the mean increase in bone mineral density was 6.0% ± 4.4% at the spine and 2.4% ± 3.2% at the total hip. Serum levels of bone turnover markers decreased versus baseline: bone alkaline phosphatase -34% and -35%, and C-terminal telopeptide -68% and -56% at 6 and 12 months, respectively. None of the patients reported new fractures during the year of follow-up. In all the first 20 treated patients, a transitory acute phase response was observed, but this was prevented in 4 of 5 subsequent patients in whom acetaminophen was given systematically during the 3 days post-infusion. CONCLUSIONS: A single 5 mg zoledronic acid intravenous infusion in patients with osteoporosis secondary to indolent systemic mastocytosis is associated with significant increases in spine and hip bone mineral density and decreases of bone turnover markers over at least 1 year. Yearly zoledronic acid might represent a therapeutic option for indolent systemic mastocytosis-associated osteoporosis.

Medication use before and after hip fracture: a population-based cohort and case-control study.

BACKGROUND: Osteoporosis, together with age, is the main risk factor for hip fracture, the incidence of which has also been associated with an increased risk of falling or co-morbidities and related pharmacological treatments. OBJECTIVES: The aim of this study was to investigate changes in concomitant pharmacological treatments prescribed before and after hip fracture in elderly patients compared with treatments prescribed to a matched cohort of subjects without hospitalisation for fractures. METHODS: Data relating to the study population were extracted from a large population-based administrative database of the Italian National Health Authorities. A retrospective analysis was conducted involving female patients (6,431) aged ≥65 years and hospitalised for a hip fracture. The control group comprised age-matched subjects (38,586) not hospitalised for fracture. Changes in drug prescriptions 1 year before and 1 year after hip fracture and differences versus controls were compared. RESULTS: Prior to the fracture, patients were taking more anti-Parkinson medications, antidepressants, medications for chronic obstructive pulmonary disease (COPD), bisphosphonates and calcium-vitamin D supplements, although the intake of the routinely monitored drug classes was significantly infrequent. Polypharmacy was less frequent in fractured women before fracture than in controls (22 vs. 25 %, respectively; P < 0.001), but it was more frequent (30 %, P < 0.001) post-fracture. The incidence of fracture was associated with a significant increase in the use of a number of drug classes: insulin, NSAIDs or analgesics, gastroprotectants, loop diuretics, ß-blockers, antidepressants, antiparkinson drugs, antiepileptics and drugs for COPD. CONCLUSION: Our study confirms a strong association between the use of some drugs (antidepressants, antiparkinson drugs, drugs for COPD) and the risk of hip fracture, but drug use is globally less common than in controls. Hip fracture is associated with a significant increase in drug use, suggesting a global deterioration of health conditions.

Bone involvement and osteoporosis in mastocytosis.

Bone involvement is frequent in patients with systemic mastocytosis. Osteoporosis is the most prevalent bone manifestation, but diffuse osteosclerosis or focal osteolytic or osteosclerotic lesions are not infrequent. The risk of osteoporotic fractures is high, especially at the spine and in men. Routine measurements of bone mineral density and vertebral morphometry are warranted. The bone turnover markers indicate the involvement of complex bone metabolism in mastocytosis-related manifestations. Bisphosphonates represent the first-line treatment for osteoporosis-related mastocytosis.

Bisphosphonates vs infliximab in ankylosing spondylitis treatment.

OBJECTIVE: The objective of this study was to evaluate if the anti-inflammatory properties of bisphosphonates and their effect on bone turnover could be useful in the treatment of AS. METHODS: Sixty patients were consecutively assigned in a 1:1 ratio in a 6-month open-label, single-centre study on active AS to receive monthly i.v. neridronate (100 mg) or standard infliximab (5 mg/kg) therapy. RESULTS: A significant reduction in the mean BASDAI was observed over 6 months of either neridronate (-1.72) or infliximab (-1.62) administration. The BASFI decreased significantly at 3 and 6 months in the neridronate arm, while in the infliximab group a significant reduction at 3 months but not 6 months was observed. The 10-cm visual analogue scale for axial pain decreased significantly and comparably at 3 and 6 months in both groups. No significant differences between treatment arms for all these changes were observed at both 3 months and the final assessment. The BASMI was not significantly modified in the neridronate or infliximab group. No significant variations of BMD were observed in the infliximab group, while in patients treated with neridronate a significant increase was observed at the lumbar spine. CONCLUSION: High i.v. doses of the amino-bisphosphonate neridronate are as effective as infliximab therapy in reducing disease activity in AS patients, with additional benefits on BMD changes. Further studies to confirm these results over a longer time frame are warranted together with the possibility to explore the long-term efficacy of a combination of lower anti-TNF doses with bisphosphonates.

Relationship between body composition and both cardiovascular risk factors and lung function in systemic sclerosis.

The aims of this study were to evaluate body composition in systemic sclerosis (SSc) and to assess its association with the traditional risk factors for atherosclerosis and parameters of lung function. Eighty-six patients affected by SSc (13 men and 73 women, mean age 58.5 years, mean disease duration 10.7 years, 31 with diffuse form and 55 with limited pattern) underwent evaluation of body composition using a dual-energy X-ray (DXA) fan beam densitometer (GE Lunar iDXA) in order to assess total and regional body fat mass and fat-free mass. Clinical features, pulmonary function parameters, and the concomitant presence of the traditional cardiovascular risk factors were recorded. Android fat resulted to be higher in SSc patients with coexistence of hypercholesterolemia (P = 0.021), hypertension (P = 0.028), and overweight/obesity (P < 0.001) and positively correlated with body mass index (P < 0.001). Forced vital capacity (FVC) was inversely correlated with android fat (P = 0.034) and with the android fat/gynoid fat ratio (P = 0.013) and positively correlated with android lean (P = 0.041); the correlations were improved when FVC data were adjusted for sex, age, disease duration, and smoking habits (P = 0.010 for android fat, P = 0.010 for android fat/gynoid fat ratio, P = 0.011 for android lean). In this study, we showed that visceral abdominal fat, measured by DXA, is correlated with the main cardiovascular risk factors and lung volumes in SSc patients. Longitudinal studies are needed to evaluate if decrease of abdominal fat would improve lung function.

High rate of disease remission in moderate rheumatoid arthritis on etanercept therapy: data from GISEA, the Italian biologics register.

The aim of this study was to evaluate the clinical outcomes of etanercept in rheumatoid arthritis (RA) patients with moderate or severe disease activity. We analyzed data from the Italian biologics register Gruppo Italiano Studio Early Arthritides (GISEA) to investigate the rate of disease remission and functional improvement, based on the 28-Joint Disease Activity Score (DAS28) and the (Health Assessment Questionnaire (HAQ) score in RA patients with moderate or severe disease activity beginning etanercept therapy. Disease was defined as severe (H-RA) with DAS28 ≥5.1 and moderate (M-RA) with DAS28 ≥3.2 to 5.1 at baseline. Patients were considered in remission if DAS28 was ≤2.6, and HAQ ≤0.5 defined normal function. We enrolled 953 RA patients, 320 with M-RA and 633 H-RA. Age and disease duration were similar in the two cohorts, but H-RA patients had significantly more comorbidities (p < 0.01) and took significantly more disease-modifying antirheumatic drugs (p < 0.001) than M-RA patients. After 1 year, the percentage of patients achieving disease remission and normal function (DAS28 ≤2.6 plus HAQ ≤0.5) was higher in M-RA (21.4 %) than in H-RA patients (14.8 %, p = 0.007), regardless of the disease duration. Additionally, female gender (p = 0.006) and H-RA class (p = 0.002) negatively predicted disease remission at 1 year. However, the drug survival rate did not differ between the two subsets. This study confirms that etanercept was effective in the treatment of active RA, but best response, in terms of disease remission and normal function ability, was greater and easier to attain in M-RA patients. These findings may aid clinicians to choose the best strategy to treat RA.

Profile of bazedoxifene/conjugated estrogens for the treatment of estrogen deficiency symptoms and osteoporosis in women at risk of fracture.

Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis. Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Results of systematic reviews and meta-analyses of randomized controlled trials have shown that both systemic estrogen therapy or hormone therapy (estrogen combined with a progestin) are useful to prevent bone loss, and they are the most effective treatment for such climacteric symptoms as hot flushes, sweating, vaginal dryness, and dyspareunia. Unfortunately, estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer, respectively. The selective estrogen receptor modulators (SERMs) result in positive estrogenic effects on bone, with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms. The combination of a SERM with estrogen as a tissue selective estrogen complex (TSEC) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms. This combination is particularly interesting from a clinical point of view, taking into account that estrogen alone did not increase breast cancer risk by the Women's Health Initiative. TSEC is hypothesized to provide the benefits of estrogen-alone therapy, with an improved tolerability profile because the SERM component can make possible the elimination of progestin. The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene (a third-generation SERM) in combination with conjugated estrogens in postmenopausal women. The conclusion is that effectively, the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women.

Sclerostin and DKK1 in primary hyperparathyroidism.

Bone formation is influenced by the Wnt pathway through effects on osteoblast functionality, and these actions are opposed by two antagonists: sclerostin and Dickkopf-1 (DKK1). Decreased levels of serum sclerostin were found after treatment with the PTH analogue teriparatide and in patients with primary hyperparathyroidism (PHPT), while treatment with teriparatide of postmenopausal osteoporosis is associated with increases in serum DKK1. We studied mineral metabolism and Wnt pathway in 21 postmenopausal women affected by PHPT and in 42 age-matched healthy women. Mean serum calcium and PTH were significantly higher and serum phosphates significantly lower in the PHPT group compared with the control group. Serum 25-OH-vitamin D (25OHD) was lower in PHPT patients and 1,25 dihydroxy-vitamin D [1,25(OH)2D] was significantly higher. Patients with PHPT had significantly higher levels of bone alkaline phosphatase (BAP) and of serum C-terminal telopeptides of type I collagene (sCTX). Serum sclerostin in PHPT was significantly lower (-26 %) and serum DKK1 significantly higher (+57 %) than in healthy control subjects. Serum PTH was positively correlated with 1,25OH2D (p < 0.001), BAP (p = 0.036), sCTX (p = 0.003), and DKK1 (p = 0.007) and negatively with 25OHD (p = 0.002) and sclerostin (p = 0.02). In PHPT patients, serum sclerostin was negatively correlated with BAP (p = 0.038) and sCTX (p = 0.07). Patients with PHPT have significantly lower sclerostin and higher DKK1 levels compared with healthy postmenopausal control subjects. Further studies are warranted in order to verify whether the balance between these two opposite effects on Wnt function might help explain the variable bone involvement among patients with PHPT.