Beneficial effects of anti-RANKL antibody in depression-like phenotype, inflammatory bone markers, and bone mineral density in male susceptible mice after chronic social defeat stress.

Multiple lines of evidence suggest a link between depression and osteoporosis in elderly people. Receptor activator of nuclear factor-κB ligand (RANKL) plays a role in the pathology of osteoporosis, and anti-RANKL antibody has been used in the treatment of osteoporosis. In this study, we investigated whether anti-mouse RANKL antibody could attenuate depression-like phenotypes, inflammatory bone markers and bone mineral density (BMD) in male susceptible mice after chronic social defeat stress (CSDS). We measured plasma levels of inflammatory bone markers, including osteoprotegerin (OPG), RANKL, and osteopontin. A single intravenous injection of anti-RANKL (2 mg/kg) elicited rapid antidepressant effects in CSDS susceptible mice. Furthermore, anti-RANKL significantly improved the increased plasma levels of RANKL and decreased OPG/RANKL ratio in CSDS susceptible mice. Moreover, anti-RANKL significantly attenuated the decreased BMD in CSDS susceptible mice. Interestingly, there is a positive correlation between anhedonia-like behavior and OPG/RANKL ratio in mice. These findings demonstrate that anti-RANKL may have beneficial effects in depression-like phenotype and abnormalities in bone functions of CSDS susceptible mice. It is, therefore, likely that anti-human RANKL antibody (i.e., Denosumab) would be a potential therapeutic drug for depression and osteoporosis.

Potential Role of L-Arginine and Vitamin E Against Bone Loss Induced by Nano-Zinc Oxide in Rats.

The purpose of this study was to illustrate the effects of zinc oxide nanoparticles (ZnO-NPs) administration on bone turnover and bone resorbing agents in rats and how L-arginine (L-arg) or vitamin E (vit E) co-administrations might affect them. Fasting rats were randomly divided into four groups (n = 10): G1-normal healthy animals; G2-ZnO-NPs-exposed rats (600 mg/kg-1/day-1); G3-ZnO-NPs-exposed rats co-administrated L-arg (200 mg/kg-1/day-1); G4-ZnO-NPs-exposed rats co-administrated vit E (200 mg/kg-1/day-1). The ingredients were orally administered daily. The body weight and food consumption of rats were recorded during the administration period and the experiment continued for three consecutive weeks. The results demonstrated that ZnO-NPs administration induced bone loss in rats as manifested by reduced activity of bone alkaline phosphatase (B-ALP) and increased level of C-terminal peptide type I collagen (CTx). The increase of inflammatory markers, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) by ZnO-NPs suggests that deleterious effects of ZnO-NPs on bone turnover were, in part, due to inflammation. Confirming to this suggestion, both L-arg and vit E reduced TNF-α and IL-6 levels and consequently decreased bone resorption as indicated by reduced serum CTx level. This study proved that ZnO-NPs can induce bone turnover, which may be reduced by L-arg or vit.E co-administration, partly by anti-inflammatory mechanism.

Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-reported physical impairment, global assessment of disease activity and pain in early rheumatoid arthritis: longitudinal results from two randomised controlled trials.

OBJECTIVES: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs). METHODS: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests. RESULTS: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs. CONCLUSIONS: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand. TRIAL REGISTRATION NUMBER: NCT00660647.

Obesity and rates of clinical remission and low MRI inflammation in rheumatoid arthritis.

OBJECTIVES: Obesity has been proposed as a risk factor for refractory rheumatoid arthritis (RA). We evaluated the impact of obesity on achieving clinical and imaging definitions of low disease activity. METHODS: This study evaluated 470 patients with RA from GO-BEFORE and GO-FORWARD randomised clinical trials. Included patients had blinded clinical disease activity measures and MRI at baseline, 24 and 52 weeks. Synovitis, osteitis and total inflammation scores were determined using the RA MRI scoring system. Multivariable logistic regression analyses compared odds of achieving Disease Activity Score using 28 joints and C-reactive protein (DAS28-CRP) remission, low component measures, or low MRI inflammation measures at 24 weeks in patients with obesity versus no obesity. RESULTS: At 24 weeks, patients with obesity were significantly less likely to achieve DAS28(CRP) remission (OR 0.47; 95% CI 0.24 to 0.92, p=0.03). In contrast, patients with obesity had similar odds of achieving low synovitis (OR 0.94; 95% CI 0.51 to 1.72, p=0.84) and inflammation scores (OR 1.16; 95% CI 0.61 to 2.22, p=0.64) and greater odds of achieving low osteitis scores (OR 2.06; 95% CI 1.10 to 3.84, p=0.02) versus normal weight patients. CONCLUSIONS: Patients with RA and obesity have lower rates of DAS28 remission but similar rates of low MRI activity compared with patients without obesity, suggesting that obesity and its associated comorbidities can bias clinical disease activity measures. TRIAL REGISTRATION NUMBER: NCT00361335 and NCT00264550; Post-results.

Utility of 8 h and time decay-corrected acquisition scintigraphy with in-vitro labeled white blood cells for the diagnosis of osteoarticular infection.

INTRODUCTION: Except in the spine, labeled white-blood cell scintigraphy (WBCS) with image acquisition up to 24 h is the nuclear medicine test of choice for diagnosing osteoarticular infection. However, distinguishing between inflammation and infection is a challenge. OBJECTIVES: The first aim of this study was to verify earlier research studies that used 4 and 24 h time decay-corrected acquisition (TDCA) to differentiate infection from inflammation. The second aim was to analyze whether 8 h acquisition (1-day protocol) yielded similar results as 20-24 h acquisition. PATIENTS AND METHODS: This was an observational study of 94 patients (22-86 years, 52 women) with suspected osteoarticular infection referred to nuclear medicine to confirm infection. WBCS and TDCA images were obtained at 30 min, 4 h, and 8 h after injection of the labeled leukocytes, with collection times of 5, 8, and 12 min, respectively. Scintigrams were classified into three protocols: protocol 1: experts read only 30 min and 4 h images; protocol 2: experts read the whole set of images (30 min, 4 h, and 8 h) with different pixel intensities (each image normalized to its own maximum activity); protocol 3: experts read the whole set of images with the same pixel intensity. Sensitivity, specificity, positive and negative predictive values, and accuracy were calculated. In patients with orthopedic implants, the interobserver reproducibility for visual analysis was calculated using the κ index. RESULTS: Infection was confirmed in 26 cases. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and κ results were as follows: protocol 1: 92.3, 50.0, 41.4, 94.4, 61.7%, 0.79; protocol 2: 92.3, 94.1, 85.7, 97.0, 93.6%, 0.80; protocol 3: 96.2, 97.1, 92.6, 98.5, 96.8%, 0.77. CONCLUSION: TDCA acquisition of WBCS at 8 h (1-day protocol) enables a faster diagnosis than 24 h acquisition. The use of TDCA with the same pixel intensity in all images enables an accurate diagnostic of osteoarticular infection, with a considerable interobserver agreement for all protocols.

Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: The SMART body composition substudy.

Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomized to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline and months 4 and 12; BMD at the spine (dual-energy X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared with the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (ßCTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p ≤ 0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and ßCTX at month 4 predicted decrease in hip BMD at month 12, whereas increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months.

Increased levels of matrix metalloproteinase-3 in the sera and synovial fluids of patients with pustulotic arthro-osteitis associated with palmoplantar pustulosis: report of 2 cases.

Pustulotic arthro-osteitis (PAO) is occasionally seen in patients with palmoplantar pustulosis (PPP); however, its pathogenesis is still obscure. Herein, two patients with PAO associated with PPP were described. Both patients developed hydrarthrosis on the knees, along with sternocostoclavicular pain. Detail examination revealed odontogenic infection in both cases. Matrix metalloproteinase-3 (MMP-3) is a useful marker reflecting the activity of rheumatoid arthritis. In this study, MMP-3 levels in the sera as well as joint fluids were examined. Serum MMP-3 levels were increased in both cases (274 ng/ml in Case 1 and 242 ng/ml in Case 2, normal; 17.3-59.7). Also, MMP-3 concentration in the joint fluids was markedly elevated (Case 1 > 80,000 ng/ml and 48,000 ng/ml in Case 2). Our studies suggest that MMP-3 may play a role in the pathogenesis of joint involvement of PPP.

Osteitic bone: a surrogate marker of eosinophilia in chronic rhinosinusitis.

BACKGROUND: Causes of osteitis in chronic rhinosinusitis (CRS) other than previous surgery are poorly defined. Patients with eosinophilic CRS (ECRS) have more severe disease and poorer outcomes despite repeated surgery. Associations between osteitis and markers of ECRS are not well described. METHODS: A cross-sectional study of CRS patients undergoing sinus surgery was conducted. Osteitis was scored radiologically using previously published measures. Associations between osteitis and histopathology, symptoms, endoscopy, CT mucosal score and seromarkers were analyzed. RESULTS: Eighty-eight patients were assessed of whom forty-five had osteitis. Patients undergoing revision surgery recorded higher osteitis scores. Patients with mucosal eosinophilia had higher osteitis score than those without. Patients with osteitis had higher serum eosinophil. Similar relationships were also found in primary surgery. Osteitis was associated with endoscopic and radiologic, but not symptomatic disease severity. CONCLUSIONS: Osteitis is associated with tissue and serum eosinophilia in both patients with and without prior surgery. Patients with these features may benefit from post-operative corticosteroid therapy to prevent osteitis.

Bone inflammation and altered gene expression with type I diabetes early onset.

Type I diabetes is associated with bone loss and marrow adiposity. To identify early events involved in the etiology of diabetic bone loss, diabetes was induced in mice by multiple low dose streptozotocin injections. Serum markers of bone metabolism and inflammation as well as tibial gene expression were examined between 1 and 17 days post-injection (dpi). At 3 dpi, when blood glucose levels were significantly elevated, body, fat pad and muscle mass were decreased. Serum markers of bone resorption and formation significantly decreased at 5 dpi in diabetic mice and remained suppressed throughout the time course. An osteoclast gene, TRAP5 mRNA, was suppressed at early and late time points. Suppression of osteogenic genes (runx2 and osteocalcin) and induction of adipogenic genes (PPARgamma2 and aP2) were evident as early as 5 dpi. These changes were associated with an elevation of serum cytokines, but more importantly we observed an increase in the expression of cytokines in bone, supporting the idea that bone, itself, exhibits an inflammatory response during diabetes induction. This inflammation could in turn contribute to diabetic bone pathology. IFN-gamma (one of the key cytokines elevated in bone and known to be involved in bone regulation) deficiency did not prevent diabetic bone pathology. Taken together, our findings indicate that bone becomes inflamed with the onset of T1-diabetes and during this time bone phenotype markers become altered. However, inhibition of one cytokine, IFN-gamma was not sufficient to prevent the rapid bone phenotype changes.

Parathormone secretion in peritoneal dialysis patients with adynamic bone disease.

The prevalence of low-turnover lesions in patients undergoing peritoneal dialysis (PD) is high. Our aims are to evaluate the prevalence of adynamic bone disease (ABD) in PD patients, analyze risk factors, and define the association of serum parathyroid hormone (PTH) levels measured under different plasma calcium concentrations with this lesion. Fifty-seven patients were studied by bone biopsy (BB). ABD was found in 63.2%, and 36.8% showed high-turnover bone disease (HTBD). Patients with HTBD had a lower prevalence of diabetes, younger age, lower accumulated oral calcium salt intake, and greater calcitriol doses, serum osteocalcin level, and ultrafiltration than patients with ABD. Both mean baseline PTH levels from the previous year and PTH level at time of BB were greater in patients with HTBD than those with ABD (357 +/- 267 pg/mL versus 89 +/- 67 pg/mL; 390 +/- 337 pg/mL versus 88 +/- 78 pg/mL, respectively; P < 0.05). However, the magnitude of the increase from baseline serum PTH levels in response to hypocalcemia was greater in patients with ABD than in those with HTBD (166.4% +/- 134% versus 83.5% +/- 73.6%; P < 0.05). We found that PTH levels less than 150 pg/mL in patients with ABD showed a sensitivity of 91. 6%, specificity of 95.2%, and positive predictive value (PPV) of 97%. In the HTBD group, PTH levels greater than 450 pg/mL had a specificity and PPV of 100%. Our data confirm that ABD is the most prevalent lesion in PD patients, and PTH secretion capacity is maintained in these patients. The definitive diagnosis and management strategies for many patients requires a BB, especially when HTBD is unlikely.

Reduction in bone formation and elevated bone resorption in ovariectomized rats with special reference to acute inflammation.

Changes in bone modeling and remodeling in the tibia of growing rats within 30 days of ovariectomy (ovx) were evaluated by histomorphometric, mechanical; and biochemical means. Three days after ovx, suppressed bone formation was seen. This was shown by reduced osteoid volume, osteoblast surface, and bone formation rate in the secondary spongiosa, and a reduced longitudinal growth rate in the growth plate. In addition, the alkaline phosphatase and tartrate-resistant acid phosphatase activity in bone marrow supernatants was suppressed in conjunction with elevated serum sialic acid levels, indicating inflammation. Although estrogen deprivation itself may provoke the inflammatory process, the serum sialic acid level in the ovx group returned to the baseline level within 5 days after surgery, while that of estradiol in the ovx group remained consistently lower. This suggests that surgical stress, not estrogen deprivation, is the primary cause of the inflammatory response shortly after ovx. A significant difference (p < 0.01) between the ovx and sham rats was seen in the osteoclast surface, which peaked on day 7 in the ovx rats. On day 14 postovariectomy, the bone formation rate peaked and remained constant until day 30. In the ovx rats, there was a sustained reduction in the serum albumin level until day 30. Estrogen deprivation may be the primary cause of these changes, because both surgical ovx and medical oophorectomy with gonadotropin-releasing hormone agonist (G(nRHa) reduce the serum albumin level. In numerous studies dealing with changes after ovx in rats, we have observed: 1) a transient reduction in bone formation in relation to inflammatory changes evoked by ovx surgery, and 2) a sustained reduction in the serum albumin level for at least 30 days after ovx that is possibly due to estrogen deprivation.

[Changes in the plasma concentration of vitamin A, vitamin E and beta-carotene in polytrauma patients and in patients with osteitis in relation to course of illness]. / Veränderungen in der Plasmakonzentration von Vitamin A, Vitamin E und beta-Karotin bei Polytraumatisierten und Patienten mit Osteitis in Abhängigkeit vom Krankheitsverlauf.

In 17 patients with osteitis and 16 polytraumatized patients changes in the plasma levels of vitamin A, vitamin E and beta-carotene were investigated. Plasma samples taken preoperatively, daily during the first three days and then twice a week postoperatively were analysed for fat-soluble vitamins by high performance liquid chromatography (HPLC). Significant changes in plasma levels of all three components depending on the outcome of injury were found in all patients. Increased levels were observed in patients that survived the injury, while in those who died a significant decrease was observed. Recommendations regarding the supplementation with these vitamins in clinical practice can not be made based on these results, but substitute might prove beneficial for vitamin E in certain types of injury.

Leukergy--a new diagnostic test for bone infection.

This new blood test for infection is based on the phenomenon of leukergy in which white cells agglomerate in the peripheral blood of patients with inflammatory diseases. It was used in 26 patients with proven bone or joint infection and was positive in 25. The leukergy test was more accurate than the ESR, white cell count or blood culture. The percentage of cells agglomerated correlated with the clinical severity of the infection and the test detected reactivation of the septic process better than the other haematological tests. It is a rapid and inexpensive method which is useful in the diagnosis and management of bone and joint infections.

[Resorbable antibiotic delivery systems in local treatment of chronic osteitis--polyglycolic acid/poly-L-lactide as drug carrier. Experimental studies in vitro]. / Resorbierbare Antibiotikumträger zur lokalen Behandlung der chronischen Osteitis--Polyglykolsäure/Poly-L-Laktid als Träger. Experimentelle Untersuchungen in vitro.

Resorbable polyglycolic acid (PGA)- and poly-L-lactic acid (PLLA) cylinders were investigated in vitro to explore their properties as an antibiotic deposit (Ciprobay, Bayer Leverkusen) with prolonged release. PGA cylinders sized 3.2 x 5 mm, 4.5 x 5 mm and 4.5 x 7 mm respectively were shaped in monofil and polyfil technique. The Ciprofloxacin concentration varied from 0.5 mg to 5.0 mg of each cylinder. The cylinders were eluated in phosphate buffer, pH-value of 7.4, at 37 degrees C. The daily antibiotic release was measured by high performance liquid chromatography. Best combinations we could find demonstrated an initial delivery of Ciprofloxacin in vitro of 67 mg/l. The average daily release was about 16 mg/l during the first 36 days. After complete hydrolysis of the PGA carriers the recovery of Ciprofloxacin reached up to 6.5% and 11.6% respectively. For 40 bioactive cylinders (size phi 3.5 mm x 5 mm, containing 4 mg Ciprofloxacin) were eluated with phosphate buffer (pH 7.4 at 37 degrees C) respectively fresh human blood plasma and tested under various conditions. A gentamicin-polymethylmetacrylate (PMMA) chain (Septopal, E. Merck, Darmstadt) was exposed to equal test conditions for comparison. The quantities of released Ciprofloxacin and Gentamicin were analysed by a microbiological method (bioassay). Initially released rates of Ciprofloxacin were measured very high (up to 180 mg/l) but decreased rapidly within the first 5 days (4.2-22.5 mg/l). The release of Gentamicin produces an initial sharp decrease in concentration during the first 3 days (from 227.5 mg/l to 77.5 mg/l); this is then followed by an almost constant release over a long period of time (about 20 mg/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency of skeletal disease, arthro-osteitis, in patients with pustulosis palmoplantaris.

Fourteen randomly selected patients with pustulosis palmoplantaris were examined to determine the frequency of skeletal involvement. Symptoms and both clinical and radiographic signs of skeletal disease occurred in five patients (36%). Four patients had erosive and/or sclerotic changes in the region of the sternoclavicular, the first sternocostal, and/or the manubriosternal joint, in two with additional ossification of the costoclavicular ligament. Two patients had spinal involvement, one paravertebral ossifications, and the other sequelae of anterior spondylodiskitis. Peripheral joint complaints without radiographically detectable erosions, but with periarticular new bone formation, occurred in three patients. The skeletal changes are probably not incidental and seems to constitute a seronegative spondyloarthropathy associated with pustulosis palmoplantaris.

[Value of the assay of C-reactive protein in osteoarticular infection]. / Intérêt du dosage de la C. réactive protéine dans l'infection ostéoarticulaire.

The C-reactive protein is specifically increased in the acute phase of inflammation. Its level in the serum is measured by the use of immunonephelometry and is obtainable after 2.5 hours. It normally ranges between 3 and 22 mg/litre. The authors have measured the C-reactive protein after 50 surgical procedures in septic cases. They have compared its levels with other biological tests such as the sedimentation rate and the leucocyte count. The variations in C-reactive protein occurred very early and were very extensive, the increase ranging between 200 and 1500 per cent after the surgical procedure. In cases without septic complications the level returned to normal within seven days, while the sedimentation rate only became normal after three months. In cases with septic complications, the rise of C-reactive protein appeared before clinical signs. Therefore, such an increase should lead to a search for a persistent infective focus or the presence of an osteitis. However, this biological test cannot differentiate between an acute infective and a severe inflammatory process.

Concentrations of oxytetracycline, tetracycline and doxycycline in mandibular osteitis.

Treatment of osteitis in the mandible after surgery is still a clinical problem. Levels of three tetracyclines--doxycycline, oxytetracycline and tetracycline--were measured in serum and dental alveolar serum in 30 patients undergoing oral surgery. The serum concentrations were higher than the dental alveolar serum concentrations in all patients. The maximal concentration in the alveolar serum for doxycycline was between 3.0 and 3.5 mug/ml while the corresponding values for oxytetracycline and tetracycline were between 1.0 and 2.0 mug/ml. When the dental alveolar serum concentrations of the various tetracycline analogues were related to their range of inhibitory concentrations for microorganisms isolated from mandibular osteitis, it was found that each drug reached levels sufficient to inhibit most but not all strains.