Assessment of osteoprotegerin and RANKL levels and several cardiovascular risk scoring systems in acromegaly.

PURPOSE: The OPG/RANKL (osteoprotegerin/receptor activator of nuclear factor kappa-B) system, which plays a crucial role in bone metabolism, is also associated with vascular calcification. Acromegaly is characterized by excessive secretion of growth hormone and insulin-like growth factor, and studies have demonstrated an elevated risk of cardiovascular disease in individuals with acromegaly. In this study, our objective was to investigate the relationship between OPG/RANKL and various cardiovascular risk scoring systems. METHODS: We recruited 44 consecutive acromegaly patients and 41 healthy controls with a similar age and gender distribution for this study. RESULTS: While RANKL levels were significantly higher in the acromegaly group compared to the controls, OPG levels were not found to be significantly different between the two groups. Furthermore, within the acromegaly group, RANKL levels were significantly higher in patients with active acromegaly compared to those with controlled acromegaly. Osteoprotegerin levels showed a positive correlation with the Framingham risk score (FRS) in the acromegaly group. Linear regression analysis revealed an association of OPG with FRS (adjusted R2 value of 21.7%). CONCLUSION: OPG and RANKL may serve as potential markers for assessment of cardiovascular calcification and prediction of the cardiovascular risk status in acromegalic patients.

Histochemical assessment of osteoclast-like giant cells in Rankl-/- mice.

OBJECTIVES: We examined mice with gene deletion of Receptor activator of nuclear factor-κB (Rank) ligand (Rankl) to histologically clarify whether they contained progenitor cells committed to osteoclastic differentiation up to the stage requiring RANK/RANKL signaling. METHODS: The tibiae and femora of ten-week-old male wild-type, c-fos-/-, and Rankl-/- mice were used for immunohistochemistry and transmission electron microscopy (TEM). RESULTS: In Rankl-/- mice, we observed osteoclast-like giant cells, albeit in low numbers, with single or two nuclei, engulfing the mineralized extracellular matrix. TEM revealed that these giant cells contained large numbers of mitochondria, vesicles/vacuoles, and clear zone-like structures but no ruffled borders. They often engulfed fragmented bony/cartilaginous components of the extracellular matrix that had been degraded. Additionally, osteoclast-like giant cells exhibited immunoreactivity for vacuolar H+-ATPase, galectin-3, and siglec-15 but not for tartrate-resistant acid phosphatase, cathepsin K, or MMP-9, all of which are classical hallmarks of osteoclasts. Furthermore, osteoclast-like giant cells were ephrinB2-positive as they were near EphB4-positive osteoblasts that are also positive for alkaline phosphatase and Runx2 in Rankl-/- mice. Unlike Rankl-/- mice, c-fos-/- mice lacking osteoclast progenitors and mature osteoclasts had no ephrinB2-positive osteoclast-like cells or alkaline phosphatase-positive/Runx2-reactive osteoblasts. This suggests that similar to authentic osteoclasts, osteoclast-like giant cells might have the potential to activate osteoblasts in Rankl-/- mice. CONCLUSIONS: It seems plausible that osteoclast-like giant cells may have acquired some osteoclastic traits and the ability to resorb mineralized matrices even when the absence of RANK/RANKL signaling halted the osteoclastic differentiation cascade.

Assessment of Serum sRANKL, sRANKL/OPG Ratio, and Other Bone Turnover Markers with the Estimated 10-Year Risk of Major and Hip Osteoporotic Fractures in Rheumatoid Arthritis: A Cross-Sectional Study.

BACKGROUND: Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. METHODS: Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. RESULTS: The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). CONCLUSION: High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.

Flavonoids from the peels of Citrus unshiu Markov. and their inhibitory effects on RANKL-induced osteoclastogenesis through the downregulation of c-Fos signaling in vitro.

Phytochemical investigation of Citrus unshiu peels led to the isolation of eight new flavonols (7-9, 11-15) and sixteen known compounds (1-6, 10, 16-24). Their structures were elucidated using spectroscopic analysis (1D, 2D NMR, and HR-MS). Besides, all isolated compounds (1-24) were evaluated for their inhibitory effects on receptor activator of RANKL-induced osteoclastogenesis in BMMs. Among them, dimethylmikanin (1), quercetogetin (2), 3,3',4',5,7,8-hexamethoxyflavone (3), 3-methoxynobiletin (4) showed a significant inhibitory effect on RANKL-induced osteoclast differentiation at a concentration of 10 µM. Moreover, 3-methoxynobiletin (4) suppressed RANKL-induced osteoclastogenesis by decreasing the number of osteoclasts and osteoclast actin-ring formation in a dose-dependent manner without causing any cytotoxic effects on BMMs. At the molecular level, 3-methoxynobiletin (4) inhibited RANKL-induced c-Fos expression and subsequently NFATc1 activation, as well as the expression of osteoclastogenesis-related marker genes c-Src and CtsK. These findings suggested that 3-methoxynobiletin (4) attenuated osteoclast differentiation by inhibiting RANKL-mediated c-Fos signaling and that it may have therapeutic potential for treating or preventing bone resorption-related diseases, such as osteoporosis.

Mitigation of Rheumatic Arthritis in a Rat Model via Transdermal Delivery of Dapoxetine HCl Amalgamated as a Nanoplatform: In vitro and in vivo Assessment.

PURPOSE: Dapoxetine HCl (DH), a selective serotonin reuptake inhibitor, may be useful for the treatment of rheumatic arthritis (RA). The purpose of this study was to investigate the therapeutic efficacy of transdermal delivery of DH in transethosome nanovesicles (TENVs). This novel delivery of DH may overcome the drawbacks associated with orally administered DH and improve patient compliance. METHODS: DH-TENV formulations were prepared using an injection- sonication method and optimized using a 33 Box-Behnken-design with Design Expert® software. The TENV formulations were assessed for entrapment efficiency (EE-%), vesicle size, zeta potential, in vitro DH release, and skin permeation. The tolerability of the optimized DH-TENV gel was investigated using a rat skin irritation test. A pharmacokinetic analysis of the optimized DH-TENV gel was also conducted in rats. Moreover, the anti-RA activity of the optimized DH-TENV gel was assessed based on the RA-specific marker anti-cyclic cirtullinated peptide antibody (anti-CCP), the cartilage destruction marker cartilage oligomeric matrix protein (COMP) and the inflammatory marker interleukin-6 (IL-6). Level of tissue receptor activator of nuclear factor kappa-Β ligand (RANKL) were also assessed. RESULTS: The optimized DH-TENV formulation involved spherical nanovesicles that had an appropriate EE- % and skin permeation characteristic. The DH-TENV gel was well tolerated by rats. The pharmacokinetics analysis showed that the optimized DH-TENV gel boosted the bioavailability of the DH by 2.42- and 4.16-fold compared to the oral DH solution and the control DH gel, respectively. Moreover, it significantly reduced the serum anti-CCP, COMP and IL-6 levels and decreased the RANKL levels. Furthermore, the DH-TENV gel attenuated histopathological changes by almost normalizing the articular surface and synovial fluid. CONCLUSION: The results indicate that DH-TENVs can improve transdermal delivery of DH and thereby alleviate RA.

Assessment of expression and specific activities of transglutaminases TG1, TG2, and FXIII-A during osteoclastogenesis.

Osteoclasts are large multinucleated bone-resorbing cells derived from monocyte/macrophage lineage. Macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) drive the multi-stage osteoclastogenesis. Transglutaminases (TGs) are Ca2+- and thiol-dependent acyl transferases and protein crosslinking enzymes. TG enzyme family contains eight catalytically active enzymes TG1-7 and Factor XIII-A (FXIII-A). Recent studies have shown that TG1, TG2, and FXIII-A are present in osteoclasts and that TG2 and FXIII-A regulate osteoclastogenesis. In this study, we examined gene and protein expression and specific activities of TG1, TG2, and FXIII-A during osteoclastogenesis using "Hitomi peptides" in a day-by-day manner. We report that TG activities are highest in the differentiation and early fusion phases and then decrease dramatically. TG activities were upregulated by M-CSF and downregulated by addition of RANKL. FXIII-A was dramatically downregulated by RANKL, suggesting its involvement in M-CSF-mediated precursor commitment phase. TG1 and TG2 proteins were present throughout osteoclastogenesis, suggesting that they may have functions in both differentiation and fusion. In summary, the three TGs likely exert distinct functions at different stages of osteoclastogenesis. Our work also demonstrates that the "Hitomi peptides" are highly specific tools for detection of distinct TGs in a system where multiple TGs are present.

Comprehensive assessment of tissue and serum parameters of bone metabolism in a series of orthopaedic patients.

Bone diseases represent an increasing health burden worldwide, and basic research remains necessary to better understand the complexity of these pathologies and to improve and expand existing prevention and treatment approaches. In the present study, 216 bone samples from the caput femoris and collum femoris of 108 patients with degenerative or dysplastic coxarthrosis, hip fracture, or osteonecrosis were evaluated for the proportion of trabecular bone (TB) and expression of parathyroid hormone (PTH) type 1 receptor (PTH1R), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL). Serum levels of PTH, OPG, soluble RANKL (sRANKL), alkaline phosphatase (AP), osteocalcin, total procollagen type-1 intact N-terminal propeptide (TP1NP), tartrate-resistant acid phosphatase type 5b (TRAP5b), sclerostin, and C-telopeptide of type-1 collagen (ICTP) were also determined. Age was positively correlated with serum levels of PTH, OPG, and sclerostin but negatively associated with TB and sRANKL. Women exhibited less TB, lower sclerostin and ICTP, and higher TRAP5b. Impaired kidney function was associated with shorter bone decalcification time, less TB, lower sRANKL, and higher serum PTH, OPG, and sclerostin. Furthermore, correlations were observed between bone PTH1R and OPG expression and between serum PTH, OPG, and AP. There were also positive correlations between serum OPG and TP1NP; serum OPG and sclerostin; serum AP, osteocalcin, and TRAP5b; and serum sclerostin and ICTP. Serum OPG was negatively associated with sRANKL. In summary, clear relationships between specific bone metabolism markers were observed, and distinct influences of age, sex, and kidney function, thus underscoring their suitability as diagnostic or prognostic markers.

Assessment of Salivary Levels of RANKL and OPG in Aggressive versus Chronic Periodontitis.

RANKL (receptor activator of nuclear factor kappa-ß ligand) and OPG (osteoprotegerin) are two proteins involved in bone remodelling. During the active phase of periodontal disease, an imbalance between the ratios of the two elements can be noticed. While the expression of RANKL is elevated compared with that of OPG, the RANKL is available to bond with RANK (receptor activator of nuclear factor kappa-ß). This study was conducted on 41 patients: 19 with generalized aggressive periodontitis, 18 with severe chronic periodontitis, and 4 periodontal healthy subjects. For each patient included, we determined the salivary levels of RANKL and OPG with the help of two Human ELISA kits. The results show that the patients affected by periodontitis, either aggressive or chronic, have significant higher values of RANKL and RANKL/OPG ratio. This values correlate with the local inflammation status.

A Prospective Assessment of Periprosthetic Bone Mineral Density and Osteoimmunological Biomarkers Variations After Total Knee Replacement Surgery.

Aseptic loosening is a major cause of premature failure of total knee replacement (TKR). Variations in periprosthetic bone mineral density (BMD) and osteoimmunological biomarkers levels could help to quantify prosthesis osteointegration and predict early aseptic loosening. The gene expression of 5 selected osteoimmunological biomarkers was evaluated in tibial plateau bone biopsies by real-time polymerase chain reaction and changes in their serum levels after TKR were prospectively evaluated with enzyme-linked immunosorbent assay for 1 yr after surgery. These variations were correlated to changes in periprosthetic BMD. Sixteen patients were evaluated. A statistically significant decrease in serum levels of Sclerostin (p = 0.0135) was observed immediately after surgery. A specular pattern was observed between dickkopf-related protein 1 and osteoprotegerin expression. No statistically significant changes were detectable in the other study biomarkers. Periprosthetic BMD did not change significantly across the duration of the follow-up. Prosthetic knee surgery has an impact on bone remodeling, in particular on sclerostin expression. Although not showing statistically significant changes, in the patterns of dickkopf-related protein 1, osteoprotegerin, and the ligand of the receptor activator of nuclear factor kappa-B symmetries and correspondences related to the biological activities of these proteins could be identified. Variation in osteoimmunological biomarkers after TKR surgery can help in quantifying prosthesis osteointegration.

MRI assessment of the bone adjacent to giant cell tumours and its association with local recurrence after intralesional curettage.

AIM: To assess the tumour border surrounding giant cell tumour of the bone (GCTB) using magnetic resonance imaging (MRI) and investigate its association with local recurrence. MATERIALS AND METHODS: Sixty-nine GCTBs in proximal tibiae and distal femurs were studied. The pathological basis of the paintbrush border sign was explored. Expression of Ki-67, matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), receptor activator of nuclear factor-κ B (RANK), and RANK ligand (RANKL) in GCTBs were investigated using immunohistochemistry. Patients treated with intralesional curettage were analysed retrospectively to investigate the prognostic role of the paintbrush border sign. The differences between rates were tested using the chi-square test or Fisher's exact test, as appropriate. RESULTS: The paintbrush border sign correlated well with infiltrative margins. The expression of MMP-9 was associated with the paintbrush border sign, and positively correlated with RANKL and VEGF expression. GCTBs with the paintbrush border sign had a higher rate of local recurrence (76.19 versus 20.59%, p<0.05). The paintbrush border sign was more common in proximal tibiae, and positively correlated with cystic change. The paintbrush border signs were detected at T1-weighted imaging, but the sign was only evident in four cases on T2-weighted imaging. CONCLUSION: Pathologically, the paintbrush border sign correlates well with invasion of the bone around GCTB. MMP-9 might play a key role in the formation of penetrating irregular margins. The paintbrush border sign is revealed as a risk factor for local recurrence of GCTB. Sagittal T1-weighted imaging is crucial to diagnose the paintbrush border sign.

Assessment of local and systemic 25-hydroxy-vitamin D, RANKL, OPG, and TNF levels in patients with rheumatoid arthritis and periodontitis.

The present study aimed to evaluate proinflammatory cytokine and vitamin D levels in rheumatoid arthritis (RA) and chronic periodontitis (CP) patients and healthy individuals before and after initial periodontal treatment. Overall, 17 CP patients with RA (RA + CP), 18 systemically healthy CP patients (CP), and 18 healthy controls (C) were included. Clinical periodontal measurements were recorded and gingival crevicular fluid (GCF) and blood samples were recorded. RA + CP and CP patients received nonsurgical periodontal treatment. Vitamin D, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor-KB ligand (RANKL), and OPG levels were determined in GCF and serum. Baseline clinical parameters were similar in all periodontitis groups (P > 0.05) but were higher than that in controls (P < 0.05). Periodontal treatment improved clinical parameters in all periodontitis groups (P < 0.05). GCF vitamin D levels were higher in RA + CP and CP groups than in healthy controls, but these levels decreased in the RA + CP group after periodontal treatment (P < 0.05). Serum RANKL and GCF TNF-α levels in RA patients decreased after periodontal treatment (P < 0.05). Within the limitations of this study, the results suggested that GCF vitamin D levels are increased in RA patients and decrease after periodontal treatment; therefore, local vitamin D levels might be an important indicator of periodontal bone loss.

New anti-resorptives and antibody mediated anti-resorptive therapy.

UNLABELLED: The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in the form of osteoporotic fractures and metastatic bone disease. In recent years there has been an increasing understanding of the pathways involved in bone metabolism relevant to osteoporosis and metastases in bone. Newer therapies may aid the management of these problems. One group of drugs, the antibody mediated anti-resorptive therapies (AMARTs) use antibodies to block bone resorption pathways. This review seeks to present a synopsis of the guidelines, pharmacology and potential pathophysiology of AMARTs and other new anti-resorptive drugs. We evaluate the literature relating to AMARTs and new anti-resorptives with special attention on those approved for use in clinical practice. Denosumab, a monoclonal antibody against Receptor Activator for Nuclear Factor Kappa-B Ligand. It is the first AMART approved by the National Institute for Health and Clinical Excellence and the US Food and Drug Administration. Other novel anti-resorptives awaiting approval for clinical use include Odanacatib. Denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases. Recent evidence suggests, however, that denosumab may have an adverse event profile similar to bisphosphonates, including atypical femoral fractures. It is, therefore, essential that orthopaedic surgeons are conversant with these medications and their safe usage. TAKE HOME MESSAGE: Denosumab has important orthopaedic indications and has been shown to significantly reduce patient morbidity in osteoporosis and metastatic bone disease.

Assessment of OPG, RANKL, bone turnover markers serum levels and BMD after treatment with strontium ranelate and ibandronate in patients with postmenopausal osteoporosis.

INTRODUCTION: The aim of this study was to evaluate quantitative changes in OPG and RANKL proteins after treatment with strontium ranelate (SR) and ibandronate in patients with postmenopausal osteoporosis. MATERIAL AND METHODS: A total of 89 women with postmenopausal osteoporosis (PO), aged 51-85 years, patients of the Outpatient Clinic of Osteoporosis of the Military Teaching Hospital in Lodz, were enrolled in the study. The patients were randomly assigned to different therapies: ibandronate and (SR). Patients of the control group received only calcium and vitamin D3 supplements. The patients' visits were repeated after three and six months. Measurements of beta-CTX (C-terminal Telopeptide of type 1 collagen), osteocalcin, RANKL, osteoprotegerin (OPG), alkaline phosphatase concentrations in serum, as well as of total 24-hour calcium and phosphate levels in serum and urine, were carried out in material collected at baseline and after three and six months of therapy. Left hip and lumbar spine densitometry was done twice (at baseline visit and after six months). RESULTS: In all three groups there were no significant differences noted in the concentrations of OPG and RANKL serum protein levels during the study period. Both negative and positive correlations or tendencies of correlations were found between OPG serum concentrations and BMD changes in the SR group. CONCLUSIONS: Both ibandronate and SR do not seem to cause any significant changes in OPG and RANKL protein serum levels during the first six months of treatment. OPG may play a role in osteoclast activity suppression in the course of treatment with ibandronate in patients with PO. OPG may play an important role in the mechanism of SR therapy and may be viewed as a potentially valuable parameter for monitoring and predicting the course of treatment with SR in PO.

A comprehensive review of denosumab for bone metastasis in patients with solid tumors.

BACKGROUND: Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis. SCOPE: Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms 'denosumab', 'RANKL inhibitor' and 'bone metastasis'. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab. FINDINGS: The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment. CONCLUSION: The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.

Changes in RANKL and osteoprotegerin expression after chronic exposure to indoor air pollution as a result of cooking with biomass fuel.

The impact of indoor air pollution as a result of cooking with unprocessed biomass on membrane-bound and serum receptor activator of nuclear factor-kappa ligand 1 (RANKL), its soluble decoy receptor osteoprotegerin (OPG) and osteoclast precursor CD14(+) CD16(+) monocytes was investigated. Seventy-four pre-menopausal women from eastern India using biomass and 65 control women who cooked with cleaner liquefied petroleum gas were enrolled. PM10 and PM2.5 levels in their indoor air were measured with real-time aerosol monitors. The levels of membrane-bound RANKL on leukocytes and percentage CD14(+) CD16(+) monocytes in the subjects' blood were assayed by flow cytometry. Soluble RANKL and OPG in serum were measured by ELISA. The results showed that PM10 and PM2.5 levels were significantly higher in the indoor air of biomass-using households. Compared with the control women, the levels of CD4(+) and CD19(+) lymphocytes and circulating granulocytes with elevated levels of membrane-bound RANKL were higher in biomass users. The serum levels of RANKL were increased by 41% whereas serum OPG was reduced by 22% among biomass users. The absolute number of CD14(+) CD16(+) monocytes was significantly increased in biomass users than the control women. After controlling for potential confounders, PM10 and PM2.5 levels were found to be positively associated with leukocyte and serum RANKL and CD14(+) CD16(+) monocyte levels, but negatively with serum OPG. From these results, we can conclude that chronic exposure to biomass smoke increased membrane-bound and soluble RANKL and circulating osteoclast precursors but decreased OPG, suggesting an increased risk of bone resorption and consequent osteoporosis in biomass-exposed women of a child-bearing age. Copyright © 2015 John Wiley & Sons, Ltd.

The Assessment of Selected Bone and Cartilage Biomarkers in Psoriatic Patients from Poland.

BACKGROUND: Psoriasis is an inflammatory disease in which joints involvement may be insidious and difficult to detect. Bone and cartilage biomarkers may be helpful in screening patients with psoriasis for psoriatic arthritis (PsA). OBJECTIVES: To assess bone and cartilage serum biomarkers in psoriasis. Methods. The study was conducted in 2014 and included 61 psoriatic patients and 30 healthy individuals. In both groups, the serum concentrations of soluble receptor activator of nuclear factor-κB ligand (sRANKL), cartilage oligomeric matrix protein (COMP), osteoprotegerin (OPG), and interleukin-20 (IL-20) were examined. Severity of skin lesions was assessed by Psoriasis Area and Severity Index (PASI), body surface area (BSA), and Physician Global Assessment (PGA) scores. RESULTS: The duration of psoriasis was from 1 year to 45 years. 22 patients suffered from concomitant PsA. The mean value of PASI was 23.1 ± 12.0 and BSA was 27.6 ± 20.6%. COMP, OPG, and IL-20 concentrations in psoriatic patients were significantly higher than in the control group. OPG/sRANKL ratio was significantly lower in PsA patients than in psoriatic patients without arthritis. CONCLUSIONS: Results of the conducted study suggest that COMP, OPG, IL-20, and OPG/sRANKL ratio may appear useful biomarkers of bone and cartilage involvement in psoriasis.

Assessment of the Effect of Methotrexate Therapy on Bone Metabolism in Patients with Rheumatoid Arthritis.

Proinflammatory cytokines and growth factors, which regulate mutual interactions between immune system cells and bone tissue cells, play a major role in the formation of bone changes in rheumatoid arthritis (RA). The aim of the work was to assess serum concentration of osteoprotegerin (OPG), RANKL, Dkk-1 and sclerostin in RA patients compared to a control group and to analyze changes of these concentrations during methotrexate (MTX) therapy. Patients enrolled in the study were 30 women of Caucasian origin aged 30-74 years with RA. Patients with active form of the disease were administered recommended doses of MTX for at least 6 months. The study group was divided into subgroup I-patients with improvement; and subgroup II-patients with no improvement. The control group consisted of 12 healthy women in the age of 41-73. Before MTX therapy, RA patients had higher levels of RANKL (644.97 ± 477.13 vs. 255.19 ± 130.26 pmol/l), lower values of OPG/RANKL (0.01 ± 0.0101 vs. 0.02 ± 0.0078) and higher levels of Dkk-1 protein (1821.32 ± 1060.28 vs. 548.52 ± 36.35 pg/ml) compared to the control group. In the analyzed group of patients (all patients receiving MTX regardless of responder non responder status) after 6 months of therapy, a statistically significant increase in the ratio of OPG/RANKL was found (0.0118 ± 0.0102 vs. 0.0141 ± 0.0118; p = 0.02). The index value of OPG/RANKL differed significantly depending on the resultant effect of treatment (0.01702 ± 0.01274 in the subgroup of improvement vs. 0.00675 ± 0.00289 in the subgroup without improvement). The difference in the mean concentrations of Dkk-1 before and after treatment with MTX between subgroups I and II was statistically significant (p = 0.002). In subgroup I, mean concentration of Dkk-1 decreased after 6 months of treatment with MTX (2054.72 ± 1004.74 vs. 1831.70 ± 851.70 pg/ml); while in subgroup II, the mean concentration of Dkk-1 increased (1214.48 ± 738.32 vs. 2275.01 ± 1385.23 pg/ml). There were no statistically significant changes in the mean concentrations of sclerostin before and after treatment with MTX (in whole group treatment with MTX, in subgroup I, and in subgroup II). The results confirm the presence of disorders of bone metabolism in patients with RA. Treatment with MTX affects the value of the ratio of OPG/RANKL and concentration of Dkk-1.

Denosumab: a review of its use in postmenopausal women with osteoporosis.

Subcutaneous denosumab (Prolia(®) [USA, Europe]; Pralia(®) [Japan]) once every 6 months is indicated in several countries for the treatment of postmenopausal women with osteoporosis at increased or high risk for fractures (featured indication). In some countries, it is also indicated for use in postmenopausal women who have failed or are intolerant to other osteoporosis treatments. In several international, phase III trials (≤3 years' duration) involving more than 12,000 women with postmenopausal osteoporosis or low bone mineral density (BMD), including Asian studies, denosumab was an effective and generally well tolerated treatment. Relative to placebo, denosumab treatment significantly reduced the risk of vertebral, nonvertebral and hip fractures and increased BMD at all skeletal sites evaluated, including the lumbar spine and total hip. Furthermore, the benefits of denosumab treatment were generally evident after the first dose and were maintained during up to 8 years of treatment in an ongoing extension study. The tolerability profile of denosumab during this extension phase was consistent with that observed during the initial 3-year FREEDOM trial. At 12 months, denosumab treatment increased BMD at the total hip, lumbar spine and/or femoral neck and reduced markers of bone turnover to a significantly greater extent than oral bisphosphonates in women who were essentially bisphosphonate-naive and in those who had switched from alendronate to denosumab treatment. Further clinical experience, including an ongoing postmarketing safety study, will more fully define the long-term safety of denosumab. In the meantime, denosumab is an important option for the treatment of women with postmenopausal osteoporosis at increased or high-risk of fractures, including in women at increased risk of fracture who are unable to take other osteoporosis treatments.

[The non-hormonal treatment of metastatic prostate cancer]. / Le traitement non hormonal de la maladie métastatique du cancer de la prostate.

AIM: To describe drugs used in the non-hormonal treatment of metastatic prostate cancer. MATERIAL: Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. RESULTS: The metabolic radiotherapy although under-used for this indication, kept a place at the beginning of the disease. Radium-223 chloride seems to have to occupy an important place in the coming years. The chemotherapy, the only recourse until very recently in the castration-resistant prostate cancer, must redefine its place partially. The denosumab provide an interesting alternative to bisphosphonates. CONCLUSION: The non-hormonal treatment of the metastatic disease of the prostate cancer is changing rapidly with the emergence of new molecules. Urologist must know perfectly these new drugs.