Long-Term Outcomes of Conventional And Novel Steroid Replacement Therapy On Bone Health In Primary Adrenal Insufficiency

Purpose: To compare dual-release hydrocortisone (DR-HC) and conventional glucocorticoids (GCs) on bone metabolism in patients with primary adrenal insufficiency (PAI).Methods: Thirty-five patients with PAI maintained conventional GCs (group A), while other 35 were switched to DR-HC (group B). At baseline and after 18, 36 and 60 months of conventional GCs and DR-HC treatment, the clinical and bone metabolic parameters were evaluated. Results: After 60 months of follow-up, patients in group A had a significant increase in Body Mass Index (BMI) (p=0.004) and Waist Circumference (WC) (p=0.026) and a significant decrease in osteocalcin (p=0.002), bone alkaline phosphatase (p=0.029), lumbar spine bone mass density (BMD) T and Z scores (p<0.001 and p=0.001, respectively) than baseline. By contrast, patients in group B had a significant decrease in WC (p=0.047) and increase in bone alkaline phosphatase (p=0.019), lumbar spine BMD T score (p=0.032), femoral neck BMD T and Z scores (p=0.023 and p=0.036, respectively) than baseline. Conclusions: Long-term conventional steroid replacement therapy is associated with a decrease in BMD, notably at lumbar spine, and an increase in vertebral fractures rate. By contrast, DR-HC treatment is associated with improvement of BMD.

Analytical evaluation of the Nittobo Medical tartrate resistant acid phosphatase isoform 5b (TRACP-5b) EIA and comparison with IDS iSYS in different clinically defined populations

Objectives Tartrate-resistant acid phosphatase, isoform 5b (TRACP-5b) is a bone resorption marker not influenced by renal function or food intake. TRACP-5b can be measured with Nittobo Medical enzymatic-immunoassay and IDS-iSYS automated immunoassay. We evaluated the Nittobo assay and established reference ranges for a Western-European population. We compared Nittobo and IDS results in different well-defined clinical populations. Methods We established the limits of detection and quantification (LOD-LOQ), linearity, imprecision and the reference ranges in 119 males, 50 women (<45 years) and 120 women (>60 years) for TRACP-5b with the Nittobo assay. We compared both assays in 30 hemodialyzed (HD), and 40 stage 3–5 patients suffering from chronic kidney disease (CKD), 40 patients suffering from rheumatoid arthritis and osteoporosis and 80 post-menopausal women. We measured TRACP-5b, β-crosslaps (β-CTX), bone alkaline phosphatase (B-ALP) and PTH in 20 hemodialyzed (HD) and 40 CKD patients. Results LOD and LOQ were 0.02 and 0.35 U/L. CV ranged from 8.3 to 4.3% (2/5 samples presenting CV > desirable CV). Method was linear up to of 11.3 U/L. Upper and lower limits of normality were 0.8–7.6 U/L in men, 0.9–4.7 U/L in women <45 and 0.9–7.1 U/L in women >60. The regression equation between the 2 methods was Nittobo = 1.13 (95% CI: 1.09–1.16) × iSYS − 0.4 (95% CI: −0.5; −0.3). TRACP-5b and b-ALP were in their respective reference ranges for most of CKD and HD patients. That was not the case for β-CTX, which increased with decreasing eGFR. Conclusions Nittobo TRACP-5b presents interesting analytical features and a good concordance with IDS iSYS. These methods could thus potentially be harmonized.

The Novel Bone Alkaline Phosphatase Isoform B1x Is Associated with Improved 5-Year Survival in Chronic Kidney Disease

Circulating alkaline phosphatase (ALP) is an independent cardiovascular risk marker. Serum bone ALP (BALP) isoforms indicate bone turnover and comprise approximately 50% of total circulating ALP. In chronic kidney disease (CKD), mortality is highest in patients with increased ALP and BALP and low bone turnover. However, not all low bone turnover states are associated with increased mortality. Chronic inflammation and oxidative stress, features of protein energy wasting syndrome, induce cardiovascular BALP activity and fibro-calcification, while bone turnover is suppressed. Circulating BALP isoform B1x is associated with low ALP and low bone turnover and has been exclusively detected in CKD. We investigated the association of serum B1x with survival, abdominal aortic calcification (AAC) score, and aortic pulse wave velocity (PWV) in CKD. Serum ALP, BALP isoforms, parathyroid hormone (PTH), PWV, and AAC were measured repeatedly over 2 years in 68 prevalent dialysis patients. Mortality was assessed after 5 years. B1x was detected in 53 patients. A competing risk analysis revealed an association of B1x with improved 5-year survival; whereas, baseline PWV, but not AAC score, predicted mortality. However, PWV improved in 26 patients (53%), and B1x was associated with variation of PWV over time (p = 0.03). Patients with B1x had lower PTH and total ALP, suggesting an association with lower bone turnover. In conclusion, B1x is associated with time-varying PWV, lower circulating ALP, and improved survival in CKD, and thus may be an indicator of a reduced cardiovascular risk profile among patients with low bone turnover.

Comparative efficacy and safety of alendronate and teriparatide in bone loss reduction and prevention of vertebral fracture in osteoporotic Chinese patients

Purpose: To compare the effect of teriparatide and alendronate (bisphosphonate, BPP) among Chinese patients with osteoporosis (OoP).Method: Chinese subjects aged > 40 years with a history of vertebral/non-vertebral osteoporotic fragility/fractures were enrolled, and administered either teriparatide (TPT 20 μg/day) subcutaneously or alendronate (BPP)10 mg orally once daily for 12 months. Bone mineral density (BMD), measured using x-ray techniques, and bone formation biomarkers such as osteocalcin [OTC] and bone alkaline phosphatase, were assessed at baseline, and after 6 and 12 months of treatment. The proportion of patients with fractures as well as fracture rate were also recorded. The safety of the drugs was evaluated based treatment emergent adverse events.Result: In Chinese men with OoP, substantially greater improvement in BMD was observed in TPT group, compared to BPP group. TPT demonstrated substantially greater improvement in OTC and, bone alkaline phosphatase than in BPP. Also, patients treated with TPT had significantly lower incidence of new fracture than BPP group during the study period, irrespective of gender distribution (relative risk reduction at 6 and 12 months was 45 and 47 % respectively). The results showed that TPT was superior to BPP in increasing BMD and bone formation biomarkers and reducing new fractures in both male and female patients with osteoporosis.Conclusion: Teriparatide is effective and safe in reducing bone loss and preventing vertebral fractures in Chinese patients with osteoporosis. Furthermore, the results show that there is no gender difference in the efficacy and safety of teriparatide in osteoporosis.

In Vivo Investigation of the Ameliorating Effect of Tempol against MIA-Induced Knee Osteoarthritis in Rats: Involvement of TGF-β1/SMAD3/NOX4 Cue

Osteoarthritis (OA) is a complex disease characterized by structural, functional, and metabolic deteriorations of the whole joint and periarticular tissues. In the current study, we aimed to investigate the possible effects of tempol on knee OA induced by the chemical chondrotoxic monosodium iodoacetate (MIA) which closely mimics both the pain and structural changes associated with human OA. Rats were administrated oral tempol (100 mg/kg) one week post-MIA injection (3 mg/50 μL saline) at the right knee joints for 21 consecutive days. Tempol improved motor performance and debilitated the MIA-related radiological and histological alterations. Moreover, it subsided the knee joint swelling. Tempol decreased the cartilage degradation-related biomarkers as matrix metalloproteinase-13, bone alkaline phosphatase (bone ALP), and fibulin-3. The superoxide dismutase mimetic effect of tempol was accompanied by decreased NADPH oxidase 4 (NOX4), inflammatory mediators, nuclear factor-kappa B (NF-κB), over-released transforming growth factor-β1 (TGF-β1). Tempol decreased the expression of chemokine (C-C motif) ligand 2 (CCL2). On the molecular level, tempol reduced the phosphorylated protein levels of p38 mitogen-activated protein kinase (MAPK), and small mother against decapentaplegic 3 homologs (SMAD3). These findings suggest the promising role of tempol in ameliorating MIA-induced knee OA in rats via collateral suppression of the catabolic signaling cascades including TGF-β1/SMAD3/NOX4, and NOX4/p38MAPK/NF-κB and therefore modulation of oxidative stress, catabolic inflammatory cascades, chondrocyte metabolic homeostasis.

Interrelationships between sclerostin, secondary hyperparathyroidism, and bone metabolism in patients on hemodialysis

Context Sclerostin is an osteocyte-derived inhibitor of bone formation and is increased in kidney failure, but its role in the pathogenesis of renal bone disease remains unknown. Objective To explore the association of serum sclerostin with bone metabolism in patients undergoing hemodialysis, with a particular focus on parathyroid hormone (PTH)-dependent and PTH-independent pathways. Design Cross-sectional and prospective cohort study. Setting and participants 654 patients undergoing hemodialysis at 10 facilities in Japan. Main outcome measures We employed multivariable linear regression to explore whether sclerostin levels were associated with metacarpal bone mineral density (BMD), intact PTH, bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b). We employed mediation analyses to explore whether and to what extent the association of PTH with bone turnover markers is mediated by sclerostin. We also compared sclerostin levels between patients with and without previous or incident fractures. Results The median sclerostin level in hemodialysis patients was 3–4-fold higher than that in healthy individuals. Higher sclerostin levels were associated with higher metacarpal BMD and lower levels of intact PTH, BAP, and TRACP-5b. However, the relationships of sclerostin with bone turnover markers were substantially attenuated after adjustment for PTH. Mediation analysis suggested that the effects of PTH on bone turnover markers were mainly direct rather than mediated by sclerostin. Sclerostin levels were not associated with previous or incident fractures. Conclusions These findings suggest that in patients undergoing dialysis, sclerostin has only a limited role in bone metabolism and may not mediate the effect of PTH on bone turnover.

The Frailty Phenotype in Hemodialysis Patients and its Association with Biochemical Markers of Mineral Bone Disorder, Inflammation and Nutrition

Introduction: Frailty is a state of increased vulnerability to physical stressors. It is common in patients with end-stage renal disease (ESRD) who are on hemodialysis (HD). The aim of this study was to analyze the presence of frailty phenotype among HD patients and to evaluate their interrelationship with different biochemical markers. Methods: For the frailty assessment the Frailty Phenotype by Fried et al. was used, where frailty was reported if three of the following criteria were met: unintentional weight loss, self-reported exhaustion, weakness, slow walking speed and low physical activity. From 281 HD patients, 126 patients were frail, 58 were pre-frail (two criteria were met) and the rest of the study population were robust (97 patients). BMI was calculated for all patients and venous blood samples were taken to determine laboratory parameters for bone alkaline phosphatase (BAP), phosphate (P), potassium (K), C-reactive protein (CRP) and albumin. Results: Patients who were on HD longer than 60 months have more characters of frailty. (p=0.019). A statistically significant positive correlations between frailty score and BAP (rho = 0.189; p = 0.001), and CRP (rho = 0.233; p < 0.001) were observed, and significant negative correlations between frailty score and albumin (rho = - 0.218; p < 0.001) and K (rho = - 0.198; p = 0.001). Conclusions: The associations of frailty with markers of mineral bone disorder, inflammation and nutrition indicate the importance of these parameters in the indirect assessment of the frailty phenotype in HD patients.