Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study.

Osteoporosis and fractures are common and invalidating consequences of chronic glucorticoid (GC) treatment. Reliable information regarding the epidemiology of GC induced osteoporosis (GIOP) comes exclusively from the placebo group of randomized clinical trials while observational studies are generally lacking data on the real prevalence of vertebral fractures, GC dosage and primary diagnosis. The objective of this study was to evaluate the prevalence and incidence of osteoporotic fractures and to identify their major determinants (primary disease, GC dosage, bone mineral density, risk factors, specific treatment for GIOP) in a large cohort of consecutive patients aged >21 years, on chronic treatment with GC (≥5 mg prednisone - PN - equivalent) and attending rheumatology centers located all over Italy. Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) is a national multicenter cross-sectional and longitudinal observational study. 553 patients suffering from Rheumatoid Arthritis (RA), Polymyalgia Rheumatica (PMR) and Connective Tissue Diseases (CTDs) and in chronic treatment with GCs were enrolled. Osteoporotic BMD values (T score <-2.5) were observed in 28%, 38% and 35% of patients with CTDs, PMR or RA at the lumbar spine, and in 18%, 29% and 26% at the femoral neck, respectively. Before GC treatment, prevalent clinical fractures were reported by 12%, 37% and 17% of patients with CTDs, PMR, or RA, respectively. New clinical fragility fractures during GC treatment were reported by 12%, 10% and 23% of CTDs, PMR and RA patients, respectively. Vertebral fractures were the prevailing type of fragility fracture. More than 30% of patients had recurrence of fracture. An average of 80% of patients were in supplementation with calcium and/or vitamin D during treatment with GCs. Respectively, 64%, 80%, and 72% of the CTDs, PMR and RA patients were on pharmacological treatment for GIOP, almost exclusively with bisphosphonates. The GIOTTO study might provide relevant contributions to clinical practice, in particular by highlighting and quantifying in real life the prevalence of GIOP and relative fractures, the frequency of the main risk factors, and the currently sub-optimal prevention. Moreover, these results emphasize the importance of the underlying rheumatic disease on the risk of GIOP associated fractures.

Glucocorticoid-induced osteoporosis: 2013 update.

Glucocorticoids are the most common cause of secondary osteoporosis leading to the so-called glucocorticoid-induced osteoporosis (GIO). A treatment with 10 mg/d of prednisone or equivalent for more than 3 months leads to a 7-fold increase in hip fractures and a 17-fold increase in vertebral fractures. The difference between bone quantity and quality in GIO makes bone mineral density measurements inadequate to detect patients at risk of fracture. The adverse effects of glucocorticoids on the skeleton derive from a direct impact on bone cells with a severe impairment of mechanical competence. Crucial to prevention of GIO is early timing of intervention. The World Health Organization has adopted a fracture prevention algorithm (FRAX) intended to estimate fracture risk in GIO. The American College of Rhematology modified its prevention and treatment guidelines taking into account the individual risk of fracture calculated in GIO on the basis of the FRAX algorithm. Recently, also a joint Guideline Working Group of the International Osteoporosis Foundation (IOF) and the European Calcified Tissue Society (ECTS) published a framework for the development of national guidelines for the management of GIO. Bisphosphonates are the first-line drugs to treat GIO; teriparatide counteracts several fundamental pathophysiologic aspects of GIO; denosumab is useful in patients with renal failure and in potentially pregnant young women. Vertebroplasty and kyphoplasty may be less beneficial in GIO than in primary involutional osteoporosis.

Long-term prospective study of osteoporotic patients treated with percutaneous vertebroplasty after fragility fractures.

SUMMARY: This paper presents a prospective study on factors that could influence fracture risk after percutaneous vertebroplasty (PVP) in 115 osteoporotic patients. The mean follow-up was 39 months. The incidence of new fractures after PVP was 27.8%. Low body mass index (BMI), bone mineral density (BMD), and vitamin D are factors associated with increased risk of new fractures. INTRODUCTION: The purpose of this study was to evaluate factors that could increase the occurrence of new vertebral fractures (VFx) after PVP. METHODS: In our prospective study, we included patients of both sexes with osteoporosis (OP) and at least one painful VFx. We performed a baseline biochemical evaluation (including vitamin D plasma levels) and collected demographic, BMD, and clinical data. One hundred fifteen patients were treated with PVP and assigned to oral bisphosphonates plus Ca and vitamin D. The patients returned to control visits after 1, 3, and 6 months and every 6 months thereafter. X-rays film of the dorsolumbar spine was repeated every 12 months, or in case of pain that would suggest VFx occurrence. RESULTS: The mean follow-up was 39 ± 16 months (range, 15-79). Thirty-two patients (27.8%) had new fragility VFx, all symptomatic. All the fractured patients agreed to undergo a new PVP. We compared the patients who had new VFx to those who had not, and we found significantly lower BMI, total hip, and femoral neck T-scores in the group with new VFx. Furthermore, baseline plasma levels of 25(OH) vitamin D (25(OH)D) were significantly lower in this group. Upon analyzing plasma levels of 25(OH)D 12 months after PVP, we found that a significant difference still persisted: 22 ± 12 (group with new VFx) vs. 41 ± 22 ng/ml (group with no VFx; p < 0.01). CONCLUSION: We found that in patients with OP treated with PVP, the incidence of new VFx was 27.8% after 39 months; low BMI, BMD, and vitamin D are factors associated with increased risk of new VFx in patients treated with PVP.

Optimising bisphosphonate treatment outcomes in postmenopausal osteoporosis: review and Italian experience.

This review aims to investigate ways to optimise treatment outcomes with bisphosphonate therapy of osteoporosis in general, and in Italian clinical practice specifically. Overall, poor adherence to bisphosphonate therapy is a major limiting factor in the treatment of osteoporosis, and is associated to a large extent with gastrointestinal adverse events. An improved patient-doctor relationship and patient motivation are critical factors to improving adherence. However, other medical interventions also play a significant role. Intermittent dosing regimens decrease gastrointestinal adverse events and improve adherence, and demonstrate at least equivalent efficacy to daily regimens. Intravenous formulations also improve gastrointestinal tolerability, and are recommended in Italy for patients at high risk of this adverse event. Other recommendations in Italy to improve treatment outcomes include a case-finding approach to identify patients most suitable for bisphosphonate therapy, thus reducing the numbers needed to treat to avoid fractures. To facilitate this, a comprehensive assessment is advocated which incorporates bone mineral density, previous fractures, parental history of fractures, corticosteroid use and the presence of other diseases associated with secondary osteoporosis.

[Prevention and treatment of glucocorticoid-induced osteoporosis in International and Italian scenarios]. / Prevenzione e trattamento dell'osteoporosi indotta da glucocorticoidi nella realtà Italiana e in quella Internazionale.

Osteoporosis (OP) and increased risk of fracture (Fx) associated with chronic glucocorticoid treatment pushed panels of experts and scientific societies to produce recommendations for both prevention and treatment of glucocorticoid-induced OP (GIO). Recently the American College of Rheumatology developed and/or endorsed their updated guidelines and recommendations for the prevention and treatment of GIO. In these recommendations the use of FRAX tool, for the 10-year probability of a major osteoporotic Fx, was integrated with other clinical risk factors to define low-, medium-, and high-risk patients. Updated approaches are delineated for post-menopausal women and men >50 years, pre-menopausal women not of childbearing potential, men <50 years and pre-menopausal women of childbearing potential with a history of a fragility Fx. Alendronate, risedronate, and zoledronic acid are the first-line choice in the majority of patients, with teriparatide as a second-line option. Concerning Italian scenarios, alendronate and risedronate are therapeutic agents currently dispensed and fully paid by the Public Health Service for the prevention and treatment of GIO in all patients >50 years, receiving >5 mg/day prednisone equivalent for >3 months; more recently teriparatide has also been included, only for those patients presenting ≥1 prevalent fragility Fx and receiving >5 mg/day prednisone equivalent for >12 months. Also zoledronic acid has been approved by Italian Agency of the Drug (AIFA, 30/08/10) for "... post-menopausal women and men chronically treated with GC ad high risk of Fx", but the drug is dispensed exclusively at the hospital.

Validation and further development of the WHO 10-year fracture risk assessment tool in Italian postmenopausal women: project rationale and description.

The threshold for pharmacological intervention for osteoporosis remains controversial. Tools predicting the future risk of new fractures are increasingly used to establish a convenient individual risk/benefit ratio for a long term treatment. FRAX® is likely to become the most widely used tool for assessing fracture risk also for the WHO endorsement. The inevitable limitations will not hamper its value. As for any tool like this a continuous process of validation and further development is highly warranted. The predictive and clinical value of FRAX® has to be tested in individual countries by exploring also the inclusion of additional specific relatively uncommon risk factors. The DeFRA project is intended to validate in a large cohort of postmenopausal women a new algorithm derived from FRAX®. Both, the coefficients of continuous variable and the gradients for clinical risk factors should not be considered as conclusive for the routine clinical use. The new tool will be offered for the routine clinical use only at the completion of the DeFRA project, requiring the prospective collection of at least 60.000 patient-years. Here we report the rational and the design of the project.

Vitamin D status and response to treatment in post-menopausal osteoporosis.

UNLABELLED: Treatment with anti-resorptive agents over 13 months was associated with for three to fivefold lower bone mineral density changes and 1.5-fold increased risk of incidence fracture in vitamin D insufficient as compared to vitamin D repleted postmenopausal osteoporotic women. INTRODUCTION: Several drugs were registered for the treatment of osteoporosis on the basis of clinical trials in which vitamin D repletion was a pre-requisite inclusion criteria and vitamin D supplements were used as adjunctive therapy. However, in routine clinical practice these supplements are not consistently recommended. METHODS: We studied 1515 women with postmenopausal osteoporosis under treatment with anti-resorbing agents (alendronate, risedronate, raloxifene) for 13.1 months with an adherence > 75%. The patients were classified as vitamin D deficient (N = 514) or vitamin D repleted (N = 1001) according to risk factors (N = 1062) or the level of 25(OH) vitamin D [25(OH)D] above or below 50 nmol/l (N = 453). RESULTS: Vitamin D deficient and vitamin D repleted subjects differed significantly for annualized spine and hip bone mineral density (BMD) changes adjusted for all available confounding factors (type of treatment, age, global calcium intake, baseline BMD values). One hundred fifty one patients suffered from a new incident clinical fracture. The adjusted odds ratio for incident fractures in vitamin D deficient as compared to vitamin D repleted women was 1.77 (1.20 - 2.59, 95% CI; p = 0.004). CONCLUSIONS: Optimal vitamin D repletion seems to be necessary to maximize the response to anti-resorbers in terms of both BMD changes and anti-fracture efficacy.

Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus.

We have examined the urinary excretion of stable immunoreactive eicosanoids in 23 female patients with systemic lupus erythematosus (SLE), 16 patients with chronic glomerular disease (CGD), and 20 healthy women. SLE patients had significantly higher urinary thromboxane B2 (TXB2) and prostaglandin (PG) E2 excretion and significantly lower 6-keto-PGF1 alpha than did healthy women. In contrast, CGD patients only differed from controls for having reduced 6-keto-PGF1 alpha excretion. The group of SLE patients with active renal lesions differed significantly from the group with inactive lesions for having a lower creatinine clearance and urinary 6-keto-PGF1 alpha and higher urinary TXB2. Higher urinary TXB2 excretion was associated with comparable platelet TXB2 production in whole blood, undetectable TXB2 in peripheral venous blood, and unchanged urinary excretion of 2,3-dinor-TXB2. A significant inverse correlation was found between urinary TXB2 and creatinine clearance rate (CCr). In contrast, the urinary excretion of 6-keto-PGF1 alpha showed a significant linear correlation with both CCr and para-aminohippurate clearance rate (CPAH). In four SLE and seven CGD patients, inhibition of renal cyclooxygenase activity by ibuprofen was associated with a significant reduction in urinary 6-keto-PGF1 alpha and TXB2 and in both CCr and CPAH. However, the average decrease in both clearances was 50% lower in SLE patients than in CGD patients, when fractionated by the reduction in urinary 6-keto-PGF1 alpha or PGE2 excretion. We conclude that the intrarenal synthesis of PGI2 and TXA2 is specifically altered in SLE. Such biochemical alterations are associated with changes in glomerular hemodynamics and may play a role in the progression of SLE nephropathy.

Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients.

OBJECTIVE: Fibromyalgia (FMS) is a chronic syndrome characterized by widespread pain, troubled sleep, disturbed mood, and fatigue. Several analgesic strategies have been evaluated but the results are moderate and inconsistent. Antidepressant agents are now considered the treatment of choice in most patients. It has been recently suggested that FMS may be associated with metabolic alterations including a deficit of carnitine. In this multicenter randomized clinical trial we evaluated the efficacy of acetyl L-carnitine (LAC) in patients with overt FMS. METHODS: One hundred and two patients meeting the American College of Rheumatology criteria for FMS were randomized into the study. The treatment consisted of 2 capsules/day of 500 mg LAC or placebo plus one intramuscular (i.m.) injection of either 500 mg LAC or placebo for 2 weeks. During the following 8 weeks the patients took 3 capsules daily containing either 500 mg LAC or placebo. The patients were seen during treatment after 2 (visit 3), 6 (visit 4) and 10 weeks (visit 5). The patients were also visited 4 weeks after treatment discontinuation (follow-up visit). Outcome measures included the number of positive tender points, the sum of pain threshold (kg/cm2 or "total myalgic score"), the Short Form 36 (SF36), a 100 mm visual analog scale (VAS) for self-perceived stiffness, fatigue, tiredness on awakening, sleep, work status, depression, and muscular-skeletal pain, and the Hamilton depression scale. RESULTS: The "total myalgic score" and the number of positive tender points declined significantly and equally in both groups until the 6th week of treatment. At the 10th week both parameters remained unchanged in the placebo group but they continued to improve in the LAC group with a statistically significant between-group difference. Most VAS scores significantly improved in both groups. A statistically significant between-group difference was observed for depression and musculo-skeletal pain. Significantly larger improvements in SF36 questionnaire were observed in LAC than in placebo group for most parameters. Treatment was well-tolerated. CONCLUSION: Although this experience deserves further studies, these results indicate that LAC may be of benefit in patients with FMS, providing improvement in pain as well as the general and mental health of these patients.

Effect of cyclosporine A on bone density in female rheumatoid arthritis patients: results from a multicenter, cross-sectional study.

OBJECTIVE: To analyze the influence of cyclosporine A (CYA) on bone using data from a large multicenter, cross-sectional study on bone mineral density (BMD) in rheumatoid arthritis (RA). METHODS: We selected 558 female patients with RA and divided them into two groups on the basis of CYA use: those who had never used CYA (n = 467) and CYA users (n = 91; users for < 24 months n = 50; users for > 24 months n = 41). Demographic, disease and treatment-related variables were collected for each patient. BMD was measured at the lumbar spine and proximal femur using dual x-ray absorptiometry. Data was analyzed by means of a univariate and multivariate statistical procedure. Osteoporosis (OP) was defined as BMD < -2.5 T score. RESULTS: The frequency of OP among non-CYA users and CYA users was 28.2% and 33.3% (p=NS) for the lumbar spine, and 34.2% and 31.3% (p=NS) for the femoral neck, respectively. The prevalence of fragility fractures was not significantly different between the two groups. Mean values for the T-score at either the lumbar spine or the femoral neck were comparable in the two groups, even after adjustment for age, menopausal status, body mass index (BMI), Health Assessment Questionnaire (HAQ) score and steroid use. The generalized linear model showed that age, BMI and the HAQ score were significant independent predictors of BMD at the lumbar and femoral levels, whereas CYA use was not. Logistic analysis showed that only age, the HAQ score and BMI were significantly associated with the risk of OP. However, the duration of CYA therapy > 24 months was associated with an adjusted decreased lumbar BMD and a significantly decreased femoral neck BMD (p = 0.01). The frequency of femoral neck OP in patients on CYA for > 24 months was significantly higher than in patients on CYA for < 24 months: 46.4% vs. 19.44% (p=0.03), while the prevalence of fragility fractures did not differ significantly: 23.1% vs. 16.6%, respectively (p=NS). Logistic analysis showed that CYA use was an independent predictor of osteoporosis at the femoral site. CONCLUSION: Long-term CYA therapy may have negative effects on BMD in female RA patients.

Quantitative ultrasound calcaneous measurements: normative data for the Italian population. the ESOPO study.

Quantitative ultrasound (QUS) is a reliable technique to evaluate skeletal status, to identify osteoporotic subjects, and to estimate the risk of fractures. The purpose of this study was to generate QUS normative data for Italian females and males aged 60-79 yr participating in the Epidemiologic Study on the Prevalence of Osteoporosis (ESOPO) study, using the Achilles Plus apparatus. ESOPO is a cross-sectional study conducted in 2000, aiming at assessing risk of osteoporosis in a random sample of 11,011 women and 4981 men, representative of the Italian population. All participants were administered a questionnaire on the most relevant risk factors for osteoporosis and fractures; 3 QUS parameters were also measured: broadband ultrasound attenuation (BUA); speed of sound (SOS); and Stiffness Index (SI). We studied the age-dependent changes in QUS values, and their correlation with body size. For both men and women, weight was the variable with the highest correlation with BUA and SI; for SOS, age among women and body mass index (BMI) among men presented the highest correlation coefficients. Average decreases of 3.0% in BUA, 0.8% in SOS, and 9.1% in SI from 60 to 79 yr were detected for females, whereas no significant changes with age in males were observed. Our data show lower QUS values for women, and a decline at a greater rate than in men.

[Study of vitamin D status of rheumatoid arthritis patients. Rationale and design of a cross-sectional study by the osteoporosis and metabolic bone diseases study group of the Italian Society of Rheumatology (SIR)]. / Studio dello stato vitaminico D in pazienti affetti da artrite reumatoide. Razionale e disegno della rilevazione cross-sectional programmata dal gruppo SIR per lo studio dell'osteoporosi e delle malattie metaboliche dello scheletro.

The fundamental role of Vitamin D has been long known in regulating calcium homeostasis and bone metabolism. An increased contribution of Vitamin D was recently described in association with a lower incidence of Rheumatoid Arthritis (RA). This must not be surprising, as the immunomodulating effects of Vitamin D are clear, which have been attributed protective effects in autoimmune disorders such as some chronic inflammatory bowel diseases, multiple sclerosis and type I diabetes. An interaction was suggested between Vitamin D metabolism and inflammation indexes through mediation of TNF-alpha which is also especially involved in osteoclastic resorption and therefore in bone loss processes. Some preliminary data would indicate an association between seasonal changes of Vitamin D serum levels, latitude and disease activity (DAS28) in RA patients. Consequently, the Osteoporosis and Metabolic Bone Diseases Study Group of SIR believes that there are grounded reasons for assessing the Vitamin D status of RA patients in order to investigate whether this is to be related to physiopathological and clinical aspects of disease other than those of bone involvement. Primary end point of the study will be to assess the levels of 25 OH Vitamin D in RA patients. Secondary endpoints will include correlation with dis-ease activity, densitometry values and bone turnover. The cross-sectional study will enroll patients of both sex genders, age ranging between 30 and 75 years according to the 1988 ACR criteria, onset of symptoms at least 2 years prior to study enrollment. Patients will be excluded suffering from osteo-metabolic diseases, liver and kidney insufficiency and those administered Vitamin D boli in the previous 12 months. Disease activity will be evaluated with the HAQ. Hemato-chemical tests and femoral and lumbar bone densitometry will be performed, unless recently undergone by patients. Blood levels of 25 OH C Vitamin D and PHT and of the two bone remodelling markers (bone alkaline phosphatase and serum CTX) will be measured, as well. Patient enrollment will start on February 2007 and will last 4 months. By the end of 2007 the study will be concluded and results will be published.

Risk factors for osteoporosis and fragility fractures in patients with systemic lupus erythematosus.

Osteoporosis (OP) and fragility fractures (FFx) are a known comorbidity in patients with systemic lupus erythematosus (SLE). This work aimed at evaluating (1) the prevalence of OP and FFx in a cohort of SLE and (2) the risk factors associated with both OP and FFx. The following data were collected from clinical charts: age, sex, menopausal status (MP), body mass index, smoking habits, disease duration, daily dose and cumulative glucocorticoids (GCs), type of organ involvement, comorbidities and medications. Data on bone metabolism, calcium and vitamin D supplementation and treatment with bisphosphonates, teriparatide or denosumab were collected, together with bone mineral density (BMD) values (measured by dual-energy X-ray absorptiometry (DXA)) and history of FFx (occurred after the onset of SLE and unrelated to trauma). OP and reduced BMD were defined according to the WHO. 186 patients were included (women 175, men 11; mean age 46.4±13 years, mean disease duration 14.9±9 years). At their last visit, 97 patients (52.2%) had a reduced BMD and 52 (27.9%) had OP. 22 patients (11.8%), all women, had at least one FFx; six patients (27.3%) were pre-menopausal. On univariate analysis, age, cumulative dose of GC, MP, therapy with antiepileptics and chronic renal failure (CRF) were correlated with OP (p<0.03); age, total amount of GC, MP, CRF, anticoagulants (AC) and antiepileptic therapy were correlated with FFx (p<0.05). The multivariate logistic model confirmed a direct association of OP and age, MP and antiepileptic therapy (p≤0.01) and of FFx and age, chronic therapy with AC and antiepileptics (p<0.03). In conclusion, low BMD is frequently observed in SLE, and FFx are observed also in premenopausal patients. Together with traditional risk factors (age, MP and GC), CRF and chronic treatments with AC or antiepileptics seem to be associated with a higher risk profile for OP and FFx occurrence.

Disease-modifying antirheumatic drugs and bone mass in rheumatoid arthritis.

This article reviews the effects of DMARDs (including biologic agents) on bone metabolism in rheumatoid arthritis (RA). At present there is no evidence that methotrexate, at least at dosages ranging from 5 to 20 mg/week, negatively affects bone mass as measured by DXA (BMD) as documented in both cross-sectional and longitudinal studies. Most studies of cyclosporine (CyA) use reporting a reduction in erosions and joint damage with no adverse effects on bone, did not measure BMD; CyA treatment is associated with a dose-dependent increase of bone turnover as well as a decrease in both animal and human studies; however, its use in RA setting at a dose < or =5 mg/Kg/ day has so far not been associated with clinical relevant adverse effects on bone metabolism. Anti-TNF-alpha agents, infliximab reduced markers of bone turnover in two longitudinal studies. Data on BMD are not available in RA; nevertheless, an increase in BMD has been documented in spondyloarthropathies with infliximab and etanercept. No clinical data concerning BMD are available on leflunomide as well as on the newer biologic agents (adalimumab, rituximab, anakinra).

Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. Ciblos Study Group.

Osteoporosis is a well-recognized adverse effect of corticosteroid therapy. This study aimed to investigate the effect of etidronate, intermittent cyclical therapy, in the prevention of corticosteroid-induced bone loss. Patients with various medical conditions starting high-dose corticosteroid therapy were enrolled in the study. The treatment had to be expected to continue for at least 12 months with the initial 90 days at a mean daily dose of at least 7.5 mg of prednisone, with subsequent treatment of at least 2.5 mg/day. One hundred seventeen patients were randomly assigned oral etidronate 400 mg/day, or placebo, for 14 days, followed by 76 days of oral calcium carbonate (500 mg elemental calcium), cycled over 12 months. The primary outcome measure was the difference in percent change from baseline in bone mineral density of the lumbar spine between the groups at the end of year 1. Secondary measures included changes in femur bone density and in biochemical markers of bone remodeling. The mean (+/- SEM) lumbar spine bone density changed 0.30 +/- 0.61% and -2.79 +/- 0.63% in the etidronate and placebo groups, respectively. The mean difference between groups after 1 yr was 3.0 +/- 0.84% (P = 0.004). The changes in the femoral neck and great trochanter were not different between the groups. There was a decrease in pyridinium crosslinks, significant from baseline at both 6 and 12 months, in the etidronate group. Osteocalcin increased in the placebo group, and difference between groups was -25.07 +/- 14.89% (P = 0.032) and -34.68 +/- 19.77% (P = 0.051), at 6 and 12 months respectively. There was no significant difference between the groups in number of adverse experiences, including gastrointestinal disorders. Etidronate intermittent cyclical therapy prevents lumbar vertebral bone loss in patients starting high-dose corticosteroid therapy.

The synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and nonsteroidal anti-inflammatory drugs.

1 The present study was undertaken to characterize the spectrum of arachidonic acid metabolites present in synovial effusions of patients with rheumatoid or psoriatic arthritis, and to compare changes in their concentration following a short-term treatment with 6alpha-methyl-prednisolone (6-MeP: 4-8 mg/day) or indoprofen (1.2 g/day), a nonsteroidal anti-inflammatory agent with proven synovial prostaglandin inhibitory effect.2 Measurements of prostaglandin E(2) (PGE(2)), thromboxane (TX) B(2), 6-keto-PGF(1alpha) and PGF(2alpha) were performed by radioimmunoassay techniques in synovial effusions obtained from 23 patients, and validated by thin-layer chromatographic analysis of the extracted immunoreactivity.3 PGE(2) and TXB(2) accounted for more than 60% of the total immunoreactivity in untreated patients. The absence of any constant ratio between the different arachidonic acid metabolites detected in synovial fluid is consistent with a heterogeneous cellular origin of these compounds.4 Indoprofen treatment was associated with a consistent reduction of synovial prostaglandin and thromboxane concentrations, ranging from 36% in the case of 6-keto-PGF(1alpha) to 90% in the case of PGE(2).5 In contrast, 6-MeP caused opposite changes on different metabolites originating via the cyclo-oxygenase pathway. Thus, 6-keto-PGF(1alpha) concentrations were reduced by 35%, PGF(2alpha) concentrations were increased by 30%, while PGE(2) and TXB(2) were unchanged following 6-MeP.6 Although the mechanism(s) underlying the failure of 6-MeP to reduce synovial PGE(2) and TXB(2) levels are uncertain, the results of the present study clearly indicate that therapeutic doses of steroidal and nonsteroidal anti-inflammatory drugs cause quite distinct changes in arachidonic acid metabolism, which might be relevant to their specific therapeutic actions and side-effects.

Vertebral bone mineral density changes in female rheumatoid arthritis patients treated with low-dose methotrexate.

OBJECTIVE: To assess vertebral bone mineral density (BMD) changes in rheumatoid arthritis (RA) patients taking low-dose methotrexate (MTX). METHODS: We evaluated in a 2-year, longitudinal study female RA patients, who had recently started a disease-modifying antirheumatic drug (DMARD), divided into two groups: group A, receiving MTX, and group B, receiving other DMARDs. Lumbar spine BMD was assessed at baseline and every year; RA activity was assessed every 3 months. RESULTS: Sixty-two patients were enrolled in the study; 40 completed the follow-up period: 22 of group A, and 18 of group B. The results after 2 years showed that both groups lost bone significantly vs baseline (p < 0.001) in a comparable fashion: group A (mean +/- SD) -3.9 +/- 4.9% vs group B -3.0 +/- 3.7% (p = NS). The patients who showed active disease lost significantly (p < 0.05) more bone (-5.5 +/- 3.8%) than those with less active disease (-1.1 +/- 3.6%), independently of their DMARD. CONCLUSION: Low-dose MTX in RA does not seem to exert relevant effects on trabecular bone.

[Applications and results of photon absorptiometry]. / Applicazioni e risultati della mineralometria a raggi fotonici.

Bone mineral content (CMO, mg/cm2) was measured at the distal radius by dual photon absorptiometry (DPA, I125, Am241) in 1.161 women (w), aged 20-87 years. Women were subdivided into different groups according to the presence and duration of menopause. For gross evaluation of spinal osteoporosis (OP), the results of spinal X-rays were graded as follows: score 0: no signs of OP; score 1: aspecific signs of OP; score 2: typical signs of OP; score 3: wedging or collapse of one or more vertebrae. Women in postmenopausal state showed significantly reduced CMO (p less than .0005) when compared to women in premenopausal state; a significant correlation was found between CMO and years since menopause (p less than .0001). Concerning the relationship between CMO and spinal score, a progressive decreases in CMO from score 0 to score 3 was present and the correlation was significant (p less than .0001). In addition, women with score 3 showed a mean CMO below the "fracture threshold", in spite of the large overlap in individual CMO values. Our data suggest that radial DPA should be maintained as a "screening" procedure for OP.

Effects of short-term, high dose, heparin therapy on biochemical markers of bone metabolism.

To evaluate the effects of the short-term, high-dose sodium heparin therapy on biochemical markers of bone metabolism, we studied 20 patients (11 males and 9 females) with pulmonary embolism, treated with sodium heparin (daily dose range: 40,000-45,000 I.U. by continuous i.v. infusion). Heparin therapy lasted 5-7 days, after which patients received warfarin over 12 months. Eleven patients (6 males and 5 females) with ischaemic stroke, treated with i.v. glycerol and pentoxifilline, were used as controls. Before and after therapy serum and urinary markers of bone metabolism were evaluated; in 12 heparin-treated pts., the parameters were also evaluated 4 months after discontinuation of warfarin therapy. After heparin therapy a significant reduction vs. basal value was observed in levels of serum osteocalcin (ng/ml;mean + SEM): 3.32 & 0.19 vs. 2.05 + 0.21; p < 0.001. In the 12 patients evaluated 4 months after discontinuation of warfarin therapy, serum osteocalcin levels returned to basal value: 3.41 + 0.12 ng/ml (p:n.s.). No significant changes of the examined parameters were observed in controls. In conclusion, our data seem to indicate an effect of i.v. short-term heparin therapy on bone metabolism. This effect seems to be characterized by an inhibition of osteoblast function as suggested by the reduction of serum osteocalcin levels.

Clinical equivalence between deflazacort oral drops and tablets in active rheumatoid arthritis.

In order to assess the clinical equivalence between deflazacort oral drops and tablets, 18 patients with active rheumatoid arthritis were enrolled in an open, controlled, randomised ('tablets --> drops' sequence, or vice versa), two-period (21 days each) crossover trial (from tablets to drops, or vice versa). Individual dose titration of deflazacort drops or tablets was made weekly on the basis of clinical need. Primary outcome measures of efficacy were changes in the joint swelling count (JSC), erythrocyte sedimentation rate (ESR), hand-grip strength (HGS), joint pain (JP), duration of morning stiffness (MS), physician's global evaluation and patient's self-assessment. Sixteen patients were available by the end of the study. The formulations were equivalent with respect to HGS and improvement in duration of MS, and close to equivalence with respect to JSC and ESR decrease; the drops seemed to be more effective than tablets with respect to JP reduction. No differences between the two formulations were observed with respect to physician's and patient's assessment. The minimum effective dose of each preparation and the relative potency ratio were also established. Drops and tablets were found to have the same potency.