Similar efficacy and safety of initial COBRA-light and COBRA therapy in rheumatoid arthritis: 4-year results from the COBRA-light trial.

Objective: To assess the efficacy and safety of initial COBRA-light vs COBRA therapy in RA patients after a 4-year follow-up period. Methods: In the COBRA-light trial, 162 consecutive patients with recent-onset RA were randomized to either COBRA-light (prednisolone and MTX) or COBRA therapy (prednisolone, MTX and SSZ) for 1 year. After 1 year, treatment was continued without protocol, and adjusted by the treating physician according to clinical judgement, preferably with a treat-to-target strategy. Four years after trial initiation, all patients were invited to participate in the COBRA-light extension study, in which patients were interviewed and physically examined, patient reported outcomes were assessed, radiographs were made and clinical records were examined for comorbidities and medication use. Results: In the extension study, 149 out of 162 (92%) original trial patients participated: 72 COBRA-light and 77 COBRA patients. Initial COBRA-light and COBRA therapy showed similar effect on disease activity, physical functioning, radiological outcome and Boolean remission over the 4-year follow-up period. In addition, both treatment groups showed similar survival and major comorbidities, although the power to detect differences was limited. Besides protocolled differences in prednisolone, MTX and SSZ use, the use of other synthetic and biologic DMARDs and intra-articular and intramuscular glucocorticoid injections was similar in both treatment groups over the 4-year period. Conclusion: Early RA patients initially treated with COBRA-light or COBRA therapy had similar efficacy and safety outcomes over a 4-year follow-up period.

The short-term effects of two high-dose, step-down prednisolone regimens on body composition in early rheumatoid arthritis.

OBJECTIVE: To investigate the effect of two different high-dose, step-down prednisolone regimens on body composition in early RA patients after 26 weeks of treatment. METHODS: Prednisolone-naive patients with recent-onset RA (n = 108) were randomized to either COBRA (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks; MTX and SSZ) or COBRA-light therapy (prednisolone 30 mg/day, tapered to 7.5 mg/day in 8 weeks and MTX). Body composition was assessed at baseline (before or soon after start of treatment) and after 26 weeks with DXA, and recorded as total body mass (TBM), total fat mass (FM), total lean mass (LM) and trunk/peripheral fat ratio. Log-ratio analyses assessed the proportional distribution of TBM (between LM, FM and bone mass) and FM (between trunk, extremities and head). The subgroup of patients with a DXA before start of treatment (n = 38) was analysed separately. RESULTS: In the subgroup of patients with a DXA before start of treatment, TBM increased by 1.6 kg (P < 0.001) and total FM by 1.3 kg (P < 0.001). The trunk/peripheral fat ratio and the proportional distribution of TBM and FM remained stable over time. There were no differences between the treatment groups. Similar results were obtained in the study population as a whole. CONCLUSION: Both high-dose, step-down prednisolone regimens caused increases in TBM, mainly caused by an increase in FM, but we found no fat redistribution from peripheral to central tissues. This absence in fat redistribution contradicts the widely held assumption of rapid adverse effects of prednisolone on body composition in RA. TRIAL REGISTRATION: ISRCTNregistry, http://www.isrctn.com, ISRCTN55552928.

Intensive combination treatment regimens, including prednisolone, are effective in treating patients with early rheumatoid arthritis regardless of additional etanercept: 1-year results of the COBRA-light open-label, randomised, non-inferiority trial.

BACKGROUND: Recently, we documented the likely non-inferiority of Combinatietherapie Bij Reumatoïde Artritis (COBRA)-light therapy (methotrexate increased to 25 mg/week with initial prednisolone 30 mg/day) compared with the original COBRA therapy (methotrexate 7.5 mg/week, sulfasalazine 2 g/day, with initial prednisolone 60 mg/day) after 26 weeks in patients with early active rheumatoid arthritis (RA). OBJECTIVE: To assess the non-inferiority of COBRA-light versus COBRA after 1 year in terms of disease activity (DAS44), functional outcome (Health Assessment Questionnaire (HAQ)) and radiographic progression (Sharp/van der Heijde score (SHS)), and to assess the effect of adding etanercept. METHODS: An open-label, randomised controlled, non-inferiority trial of 162 patients with active early RA, following a treat-to-target protocol incorporating the addition of etanercept if DAS44 ≥1.6 at weeks 26 or 39. RESULTS: Both groups showed major improvements in DAS44 after 52 weeks: mean (SD) -2.41 (1.2) in the COBRA and -2.02 (1.0) in the COBRA-light group (p=ns). In both groups, functional ability improved and radiological progression of joints was minimal. At least one adverse event was reported in 96% of the patients in both groups. In total, 25 serious adverse events occurred: 9 vs 16 in COBRA and COBRA-light, respectively. Treatment actually instituted was often less intensive than required by the protocol: of the total population, 108 patients (67%) required etanercept (more in the COBRA-light group), but only 67 of these (62%) actually received it. CONCLUSIONS: Intensive COBRA or COBRA-light therapy has major, comparably favourable effects on disease activity, functional ability and radiological outcome after 1 year in patients with early RA. Protocolised addition of etanercept was often not implemented by treating rheumatologists, and patients receiving it appeared to have limited added benefit, probably because of low disease activity levels at its initiation. TRIAL REGISTRATION NUMBER: ISRCTN55552928.

A non-inferiority trial of an attenuated combination strategy ('COBRA-light') compared to the original COBRA strategy: clinical results after 26 weeks.

BACKGROUND: Early, intensive treatment of rheumatoid arthritis (RA) with the combination of (initially high dose) prednisolone, methotrexate and sulfasalazine (COBRA therapy) considerably lowers disease activity and suppresses radiological progression, but is infrequently prescribed in daily practice. Attenuating the COBRA regimen might lessen concerns about side effects, but the efficacy of such strategies is unknown. OBJECTIVE: To compare the 'COBRA-light' strategy with only two drugs, comprising a lower dose of prednisolone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks) to COBRA therapy (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day). METHOD: An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, all treated according to a treat to target strategy. RESULTS: At baseline patients had moderately active disease: mean (SD) 44-joint disease activity score (DAS44) 4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light. After 6 months, DAS44 significantly decreased in both groups (-2.50 (1.21) for COBRA and -2.18 (1.10) for COBRA-light). The adjusted difference in DAS44 improvement between the groups, 0.21 (95% CI -0.11 to 0.53), was smaller than the predefined clinically relevant difference of 0.5. Minimal disease activity (DAS44 <1.6) was reached in almost half of patients in both groups (49% and 41% in COBRA and COBRA-light, respectively). CONCLUSIONS: At 6 months COBRA-light therapy is most likely non-inferior to COBRA therapy. CLINICAL TRIAL REGISTRATION NUMBER: 55552928.

Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation reduction.

OBJECTIVE: To investigate the dose-related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA). METHODS: A randomized, controlled, single-blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUC(G) ) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed. RESULTS: Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m(2) and 25.4 ± 4.2 kg/m(2) , respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C-reactive protein [CRP] level 14 mg/liter [interquartile range 6-34] and 19 mg/liter [interquartile range 3-39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUC(G) with erythrocyte sedimentation rate (ß = 2.430 [95% confidence interval 0.179-4.681], P = 0.04) and with CRP level (ß = 2.358 [95% confidence interval 0.210-4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUC(G) did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUC(G) (ß = 3.626 [95% confidence interval 1.077-6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017-1.122], P = 0.009). CONCLUSION: In this study, short-term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.

Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with rheumatoid arthritis.

Bortezomib (BTZ), a registered proteasome inhibitor (PI) for multiple myeloma, has also been proposed as a potential antirheumatic agent. Its reported side effects, however, make it unappealing for long-term administration, and resistance may also develop. To overcome this, second-generation PIs became available. Here, we investigated whether a novel class of peptide epoxyketone-based PIs, including carfilzomib, N-((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (ONX0912), and (S)-3-(4-methoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (ONX0914), might escape two established BTZ-resistance mechanisms: 1) mutations in the proteasome ß5 subunit (PSMB5) targeted by these PIs, and 2) drug efflux mediated by ATP-binding cassette transporters. THP1 myeloid sublines with acquired resistance to BTZ (54- to 235-fold) caused by mutations in the PSMB5 gene displayed marked cross-resistance but less pronounced cross-resistance to carfilzomib (9- to 32-fold), ONX0912 (39- to 62-fold), and ONX0914 (27- to 97-fold). As for ATP-binding cassette transporter-mediated efflux, lymphoid CEM/VLB cells with P-glycoprotein (Pgp)/multidrug resistance 1 overexpression exhibited substantial resistance to carfilzomib (114-fold), ONX0912 (23-fold), and ONX0914 (162-fold), whereas less resistance to BTZ (4.5-fold) was observed. Consistently, ß5 subunit-associated chymotrypsin-like proteasome activity was significantly less inhibited in these CEM/VLB cells. Ex vivo analysis of peripheral blood mononuclear cells from therapy-naive patients with rheumatoid arthritis revealed that, although basal Pgp levels were low, P-glycoprotein expression compromised the inhibitory effect of carfilzomib and ONX0914. However, the use of P121 (reversin 121), a Pgp transport inhibitor, restored parental cell inhibitory levels in both CEM/VLB cells and peripheral blood mononuclear cells. These results indicate that the pharmacologic activity of these PIs may be hindered by drug resistance mechanisms involving PSMB5 mutations and PI extrusion via Pgp.

Advances in glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) is one of the most important side effects of glucocorticoid use, as it leads to an increased risk of fractures. Recently, many published studies have focused on the cellular and molecular mechanisms of bone metabolism, the pathophysiology of GIOP, and the intervention options to prevent GIOP. In this review, recent advances in GIOP are summarized, particularly recent progress in our understanding of the mechanisms of GIOP resulting in improved insight that might result in the development of new treatment options in the near future.

First Report of IgG4 Related Disease Primary Presenting as Vertebral Bone Marrow Lesions.

IgG4-related disease is a fibro-inflammatory disorder characterized by swelling of tissues and affected organs accompanied by the development of scar tissue (fibrosis) and infiltration by IgG4 positive plasma cells. Almost any organ can be affected, including, but rarely, bone marrowinvolvement. Here we present a case of a 76-year-old male with IgG4-related disease presenting primarily with vertebral bone marrow lesions. Histopathology showed the typical features of storiform fibrosis, and increased IgG4 positive plasma cells. Treatment with corticosteroids significantly improved wellbeing and resolved lesion size on MRI.

Cost-utility of COBRA-light versus COBRA therapy in patients with early rheumatoid arthritis: the COBRA-light trial.

OBJECTIVE: To evaluate if COmbinatie therapie Bij Reumatoïde Artritis (COBRA)-light therapy is cost-effective in treating patients with early rheumatoid arthritis (RA) compared with COBRA therapy. METHODS: This economic evaluation was performed next to the open-label, randomised non-inferiority COBRA-light trial in 164 patients with early RA. Non-responders to COBRA or COBRA-light received etanercept (50 mg/week) for 3-6 months. The societal perspective analysis took medical direct, non-medical direct and indirect costs into account. Costs were measured with patient cost diaries for the follow-up period of 52 weeks. Bootstrapping techniques estimated uncertainty around the cost-effectiveness ratios, presented in cost-effectiveness planes. RESULTS: 164 patients were randomised to either COBRA or COBRA-light strategy. At week 52, COBRA-light proved to be non-inferior to COBRA therapy on all clinical outcome measures. The results of the base-case cost-utility analysis (intention-to-treat analyses) revealed that COBRA-light strategy is more expensive (k€9.3 (SD 0.9) compared with COBRA (k€7.2 (SD 0.8)), but the difference in costs were not significant (k€2.0; 95% CI -0.3 to 4.4). Also, both strategies produced similar quality-adjusted life-years (QALYs). The sensitivity analyses showed robustness of these results. In a per-protocol sensitivity analysis, in which costs of etanercept were assumed to be provided as prescribed according to protocol, both arms had much higher costs: COBRA-light: k€11.5 (8.3) compared with k€8.5 (6.8) for COBRA, and the difference in costs was significant (k€2.9; 0.6 to 5.3). CONCLUSIONS: In the base-case cost-utility analysis, the two strategies produced similar QALYs for similar costs. But it is anticipated that if protocol had been followed correctly, the COBRA-light strategy would have been more costly due to additional etanercept costs, for a limited health gain. Given the limited added benefit and high costs of starting etanercept in the presence of low disease activity in our trial, such a strategy needs better justification than is available now. TRIAL REGISTRATION NUMBER: 55552928, Results.

Do Short and Sustained Periods of American College of Rheumatology/European League Against Rheumatism Remission Predict Functional and Radiographic Outcome in Early Rheumatoid Arthritis Patients With Low Overall Damage Progression?

OBJECTIVE: To investigate whether remission at single and consecutive visits predicts good outcome in early rheumatoid arthritis (RA). METHODS: The presence of remission according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) and other criteria (Boolean clinical, Clinical Disease Activity Index, Disease Activity Score [DAS], DAS in 28 joints, and Routine Assessment of Patient Index Data 3) was assessed in early RA patients during the first year of the Combination Therapy for Rheumatoid Arthritis light trial. Likelihood ratios were used to assess whether meeting the remission criteria at single visits (13, 26, 39, or 52 weeks) and consecutive visits (13 and 26, 26 and 39, or 39 and 52 weeks) predicted good outcome in the second year (52-104 weeks). Good outcome was defined for function (Health Assessment Questionnaire score consistently ≤0.5 and no deterioration), radiographic damage progression (no deterioration in Sharp/van der Heijde scores), and both ("overall good outcome"). RESULTS: Of the original 164 trial patients, 144 had evaluable data. In the second year, good functional outcome was observed in 35%, good radiographic outcome in 79%, and both in 28% of the patients. Almost all criteria predicted good functional and good overall outcome, at both single and consecutive visits; only single DAS remission did not significantly predict good overall outcome (P = 0.07). Sustained remission periods resulted in higher likelihood ratios than remission at single visits. None of the criteria predicted good radiographic outcome. CONCLUSION: Early RA patients who reached remission according to ACR/EULAR and other criteria during short or sustained periods were likely to retain good physical function in the subsequent months. Sustained remission periods were a stronger predictor than remission at single visits. However, in the setting of low overall damage progression, (sustained) remission was not predictive of good radiographic outcome.

Effective Treatment for Rapid Improvement of Both Disease Activity and Self-Reported Physical Activity in Early Rheumatoid Arthritis.

OBJECTIVE: To investigate the longitudinal relationship between disease activity and self-reported physical activity (PA) in patients with early rheumatoid arthritis during the first year of treatment with combination therapy. METHODS: PA was measured with the Short Questionnaire to Assess Health-Enhancing Physical Activity at baseline, 13 weeks, 26 weeks, and 52 weeks after start of treatment in the context of the Combinatietherapie Bij Reumatoïde Artritis-Light trial. The reported PA classified patients as meeting or not meeting the World Health Organization (WHO) PA guideline (cutoff: 150 minutes of moderate-to-intense activity per week). Other measurements included the Disease Activity Score (DAS). Since both treatment arms showed equal treatment effect, these were analyzed as 1 group with simple before-after analyses and generalized estimating equations (GEE). RESULTS: In these analyses, 140 patients (86% of the trial population, 66% women, mean age 52 years) with complete data were included. At entry, 69% of the patients met the WHO PA guideline, increasing to 90% at week 13, and remaining stable at 89% after 1 year (P < 0.001). Mean DAS improved from 4.0 to 1.8 during the first year of treatment (P < 0.001). In GEE analyses, DAS decreases were significantly associated with PA increases (P = 0.008). Patients with clinically relevant responses (expressed as DAS remission, European League Against Rheumatism good response or American College of Rheumatology criteria for 70% improvement response) showed higher PA levels compared to nonresponders, regardless of the definition of response, for both the WHO and Dutch PA guideline. CONCLUSION: Early rheumatoid arthritis patients using combination therapy improved both disease activity and PA, a beneficial effect persisting for at least 1 year.

Progression of HIV to AIDS: a protective role for HLA-B27?

HLA-B27 is known for its strong association with inflammatory spondyloarthropathies (SpA), a group of rheumatic diseases. Apart from playing its role in the onset of these inflammatory diseases, HLA-827 is so ubiquitous in the world that the carrying of this gene must have also have an advantage. There are some indications that a beneficial effect can be found as a less severe course of viral infections among B27-carriers. The literature on this subject was reviewed and revealed a favorable course of infection with influenza virus, herpes simplex type 2 virus, Epstein-Barr virus and, even more interesting, a protective effect of HLA-B27 in the progression of HIV infections. The course of HIV infection differs among individuals and is thought to be partly related to host-factor variability, reflecting broad genetic heterogeneity. The polymorphic human leukocyte antigens (HLA) are herein analyzed intensively with respect to this relationship. Cytotoxic T lymphocyte (CTL) responses, activated by HLA antigen presentation, are implicated in the control of HIV replication. An immunological explanation for the protective role for HLA B27 in HIV disease is that B27+ patients have a specific and strong CTL response against the p24 epitope, a conservative HIV protein that does not easily mutate. Some HLA genes seen in long-term non-progressors (LTNP) (>10 years disease free) are associated with a favorable prognosis. One of the alleles found predominantly in LTNPs is HLA-B27. More genetic factors seem to influence disease progression in HIV infections. Therefore, it would be interesting to further explore the influence of the genetic make up of these HIV-infected individuals. Knowledge of the immunogenetic profile might give clues for the individual course of the HIV infection, may influence the development of drug-resistant viruses and will possibly lead to a tailored therapeutic strategy in HIV-infected persons.

Low grade inflammation is associated with lower velocity of sound and broadband ultrasound attenuation in older men, but not with bone loss or fracture risk in a longitudinal aging study.

OBJECTIVES: Elevated systemic levels of pro-inflammatory cytokines involved in the pathogenesis of osteoporosis. Our objective was to investigate whether low grade systemic inflammation was associated with bone markers, bone quality, bone mass and fracture risk in a population of older persons. METHODS: Serum interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR) were measured in 1287 participants of the Longitudinal Aging Study Amsterdam (LASA), a population based study in a representative sample of older men and women (age 76 ± 6.7 years). Bone quality was measured by quantitative ultrasound measurements (QUS) at baseline and after 3 years at the calcaneus, and bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) at the spine and hip in a subpopulation. Furthermore, the bone markers osteocalcin (OC) and urinary excretion of deoxypyridinoline (DPD) were determined. Incident clinical fractures were recorded during 6 years of follow-up. RESULTS: Multivariable regression analyses revealed higher IL-6 and ESR levels were associated with lower quantitative ultrasound values in older men (ß=-0.98; 95% CI -57.72 to -6.42, p<0.05) and (ß=-0.221; 95% CI -15.39 to -3.27, p<0.05) respectively at baseline, but not in women. No significant associations were found between inflammatory markers and bone markers, bone loss at the spine or hips, fracture rate or time to fracture. CONCLUSION: Elevated inflammatory markers are associated with impaired bone quality in older men, but not in women. No associations were found with the risk for fractures.

Subclinical synovitis detected by macrophage PET, but not MRI, is related to short-term flare of clinical disease activity in early RA patients: an exploratory study.

INTRODUCTION: Residual subclinical synovitis can still be present in joints of rheumatoid arthritis (RA) patients despite clinical remission and has been linked to ongoing radiological damage. The aim of the present study was to assess subclinical synovitis by positron emission tomography (PET; macrophage tracer (11)C-(R)-PK11195) in early RA patients with minimal disease activity without clinically apparent synovitis (MDA); and its relationship with clinical outcome and magnetic resonance imaging (MRI), respectively. METHODS: Baseline PET and MRI of hands/wrists were performed in 25 early MDA RA patients (DAS 44 < 1.6; no tender/swollen joints) on combined DMARD therapy. PET tracer uptake (semi-quantitative score: 0-3) and MRI synovitis and bone marrow edema (OMERACT RAMRIS) were assessed in MCP, PIP and wrist joints (22 joints/patient; cumulative score). RESULTS: Eleven of 25 patients (44 %) showed enhanced tracer uptake in ≥ 1 joint. Fourteen of these 25 (56 %) patients developed a flare within 1 year: 8/11 (73 %) with a positive, and 6/14 (43 %) with a negative PET. In the latter, in 5/6 patients flare was located outside the scan region. Median cumulative PET scores of patients with a subsequent flare in the hands or wrists were significantly higher than those of patients without a flare (1.5 [IQR 0.8-5.3] vs 0.0 [IQR 0.0-1.0], p = 0.04); significance was lost when all flares were considered (1.0 [IQR 0.0-4.0] vs 0.0 [IQR 0.0-1.0], p = 0.10). No difference in cumulative MRI scores was observed between both groups. CONCLUSIONS: Positive PET scans were found in almost half of early RA patients with MDA. Patients with a subsequent flare in hand or wrist had higher cumulative PET scores but not MRI scores, suggesting that subclinical arthritis on PET may predict clinical flare in follow-up.

(Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis.

INTRODUCTION: Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms. METHODS: A systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized. RESULTS: Seventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation. CONCLUSIONS: The current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk.

Exercise-induced changes in interleukin-10 in patients with knee osteoarthritis: new perspectives?

Osteoarthritis (OA) of the knee is a common chronic disease leading to increased morbidity and reduced quality of life. Although exercise therapy has been shown to be beneficial for both pain and physical functioning, its underlying mechanism is not fully understood. However, a recent study found an exercise-induced increase in interleukin-10 levels, to which anti-inflammatory and chondroprotective properties are ascribed, in the (peri-)synovial fluid of patients with knee OA. These interesting results provide more insight into the effects of exercise in OA and need to be validated and confirmed. Hopefully, the study offers a promising basis for further research.

Patient preference and acceptability of calcium plus vitamin D3 supplementation: a randomised, open, cross-over trial.

UNLABELLED: Preference for a drug formulation is important in adherence to long-term medication for chronic illnesses such as osteoporosis. We investigated the preference for and acceptability of chewable tablet containing calcium and vitamin D (Calci Chew D(3), Nycomed) compared to that of a sachet containing calcium and vitamin D(3) (Cad, Will-Pharma). This open, randomised, cross-over trial was set up to compare the preference and acceptability of two calcium plus vitamin D(3) formulations (both with 500 mg calcium and 400/440 IU vitamin D3), given twice a day in patients with osteoporosis. Preference and acceptability were assessed by means of questionnaires. Preference was determined by asking the question, which treatment the patient preferred, and acceptability was measured by scoring five variables, using rating scales. Of the 102 patients indicating a preference for a trial medication, 67% preferred the chewable tablet, 19% the sachet with calcium and vitamin D(3,) and 15% stated no preference. The significant preference for Calci Chew D(3) (p < 0.0001) was associated with higher scores for all five acceptability variables. The two formulations were tolerated equally well. A significant greater number of patients considered the chewable tablet as preferable and acceptable to the sachet, containing calcium and vitamin D(3). TRIAL REGISTRATION: Current Controlled Trials ISRCTN18822358.