Serum Bone-specific Alkaline Phosphatase Research Articles

Effect of Glucosamine Hydrochloride Combined with Celecoxib on Inflammatory Response and Bone Metabolism in Patients with Knee Osteoarthritis

Background: Knee osteoarthritis is one of the common chronic degenerative joint diseases. The present study explored the efficacy of glucosamine hydrochloride combined with celecoxib in the treatment of knee osteoarthritis and its effect on inflammatory response and bone metabolism. Material and Methods: Ninety patients with knee osteoarthritis were randomly divided into the single treatment group and the combined treatment group, which received the treatment using single glucosamine hydrochloride and glucosamine hydrochloride combined with celecoxib for three months, respectively. Results: After treatment, compared with the single treatment group, in the combined treatment group the total effective rate was increased, the Visual Analogue Scale score was decreased, the Lysholm score was increased, the serum tumor necrosis factor-α, interleukin 6 and interleukin 1β levels were decreased, the serum β-C-telopeptides of type I collagen level was decreased, and the serum bone-specific alkaline phosphatase and osteocalcin levels were increased. The incidence of adverse reactions during treatment had no significant difference between two groups. Conclusions: Glucosamine hydrochloride combined with celecoxib has a good therapeutic efficacy for patients with knee osteoarthritis, and it can improve the bone metabolism and reduce the inflammatory response in patients.

Bone turnover biomarkers reflect radiation-induced bone injuries in women with non-metastatic rectal cancer.

Preoperative radiotherapy (RT) for non-metastatic rectal cancer reduces local recurrence rates but can cause pelvic insufficiency fractures. Despite the high morbidity from RT-induced skeletal injuries, predictive and preventive measures are lacking. How these injuries are reflected by bone biomarkers are largely unknown. The aim was to assess longitudinal changes in bone biomarkers and their relation to RT-related bone injuries in women with rectal cancer. This longitudinal cohort study includes 47 women with non-metastatic rectal cancer treated with surgery ± preoperative RT with or without chemotherapy. Sclerostin, bioactive sclerostin, C-terminal telopeptide cross-links of collagen type I (CTX), bone-specific alkaline phosphatase (BALP), and type I procollagen intact N-terminal propeptide (PINP) were measured at baseline, after RT, and 1 yr postoperatively. Pelvic magnetic resonance imaging was used for detection of skeletal injury. Sixteen of 36 (44%) irradiated women had radiation-induced bone injuries and were compared to 11 women (RT-) and 20 women (RT+) without bone injuries. Serum CTX, BALP, and PINP increased during the first year after RT in women with radiation-induced bone injuries. The difference in mean change of CTX (p=.037) and BALP (p=.042) was conferred by longitudinal regression analyses adjusted for serum estradiol. Serum sclerostin and bioactive sclerostin remained stable over time. Taken together, bone markers may be of interest for future research on fracture prediction or preventive measures in women susceptible to radiation-induced bone injury. Due to few measure points, the full pattern cannot be captured regarding the relation over time between bone biomarkers and skeletal injury from irradiation.

Microalgae polyphosphate nanoparticles deliver bioavailable calcium against phytate antagonism: Ex vivo and in vivo studies

Biogenic nanoparticles are promising carriers to deliver essential minerals. Here, calcium-enriched polyphosphate nanoparticles (CaPNPs) with a Ca/P molar ratio > 0.5 were produced by Synechococcus sp. PCC 7002 in the growth medium containing 1.08 g/L CaCl2, and had nearly spherical morphologies with a wide size distribution of 5–75 nm and strongly anionic surface properties with an average ζ-potential of –39 mV, according to dynamic light-scattering analysis, transmission and scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The ex-vivo ligated mouse ileal loop assays found that calcium in CaPNPs was readily available to intestinal absorption via both ion channel-mediated and endocytic pathways, specifically invoking macropinocytic internalization, lysosomal degradation, and transcytosis. Rat oral pharmacokinetics revealed that CaPNPs had a calcium bioavailability approximately 100 % relative to that of CaCl2 and more than 1.6 times of that of CaCO3. CaPNPs corrected the retinoic acid-induced increase in serum calcium, phosphorus, and bone-specific alkaline phosphatase, and decrease in serum osteocalcin, bone mineral content/density, and femoral geometric parameters with an efficacy equivalent to CaCl2 and markedly greater than CaCO3. In contrast to CaCl2, CaPNPs possessed desirable resistance against phytate’s antagonistic action on calcium absorption in these ex vivo and in vivo studies. Overall, CaPNPs are attractive as a candidate agent for calcium supplementation, especially to populations on high-phytate diets.

Impact of the arginine silicate inositol complex on bone metabolism in broiler chickens with tibial dyschondroplasia caused by manganese deficiency

ABSTRACT 1. Tibial dyschondroplasia (TD) is a skeletal disorder in broilers that has financial implications, necessitating dietary modifications to reduce the prevalence of this disease. This study explored how arginine silicate inositol complex (ASI) supplementation affected tibial growth plate (TGP) and overall bone health in broilers with manganese (Mn) deficiency-induced TD. 2. A total of 240 broiler chicks were divided into four groups, each consisting of 60 birds (15 replicates of four broilers each) as follows: i) Control, with 60 mg Mn per kg of diet; ii) ASI, with 60 mg Mn and 1 g ASI per kg of diet; iii) TD, with 22 mg Mn per kg of diet, and iv) TD+ASI, with 22 mg Mn and 1 g ASI per kg of diet. 3. It was found that ASI supplementation increased tibial bone length in Mn-deficient TD broilers (p = 0.007). There was no Mn x ASI interaction for other bone morphometry variables (p > 0.05). However, both tibial bone mineral content and density were affected by Mn and ASI (p < 0.05). With ASI supplementation, serum bone-specific alkaline phosphatase and osteocalcin levels were elevated in the TD+ASI group compared to the TD group (p < 0.001). In the TD group, osteoprotegerin (OPG) levels in the TGP decreased compared to the control groups (p < 0.001). 4. In contrast, ASI supplementation in the TD broilers counteracted the decrease in OPG compared to TD broilers without ASI supplementation (p < 0.001). The Mn level and ASI supplementation significantly influenced the OPG/receptor activator of the nuclear factor-κB ligand ratio (p < 0.001). 5. In conclusion, the results demonstrated that inclusion of ASI in broiler diets could enhance bone formation variables by controlling OPG levels in the TGP, potentially serving as an effective method to decrease the occurrence of TD.

Korelacija između rizika od dentalne fluoroze i specifične alkalne fosfataze za kosti, osteokalcina, matriks metaloproteinaze i parathiroidnog hormona kod dece

Background: The aim of this study was to investigate the association between dental fluorosis occurrence in children and bone metabolism-related indicators, including bone-specific alkaline phosphatase (BALP), osteocalcin (OC), matrix metalloproteinase (MMP-2, MMP-9, MMP-20), and parathyroid hormone (PTH). Methods: A total of 189 cases of school-age children who underwent health examinations in our hospital were enrolled, according to the presence or absence of dental fluorosis. They were divided into the fluorosis group (n=97) and fluoride-free group (n=92), and the serum BALP, OC, MMP-2, MMP-9, MMP-20, and PTH levels of the two groups were compared and relevant clinical data were collected. This study employed multivariate logistic regression to examine the factors associated with the development of dental fluorosis in children. Results: The urine fluoride levels, BALP, MMP-2, and MMP9 of the children in the fluorosis group were higher than fluoride-free group, and the mother's educational level, per capita annual household income, OC, and PTH were lower than fluoride-free group (P&lt;0.05). Based on Spearman correlation analysis, a positive correlation was identified between the urinary fluoride level, the extent of dental fluorosis, and indicators such as BALP, MMP-2, and MMP-9. (r=0.618, 0.558, 0.567, 0.597, 0.602, 0.571, P&lt;0.001), and negatively correlated with OC and PTH (r=-0.580, -0.603, -0.549, -0.515, P&lt;0.001). As the urinary fluoride level and the extent of dental fluorosis increased, there was a gradual elevation in serum BALP, MMP-2, and MMP-9 levels in children, while OC and PTH levels gradually decreased (P&lt;0.05). After adjusting for confounding factors, including urinary fluoride, maternal education level, and per capita annual household income, multivariate Logistic regression analysis showed that BALP, OC, MMP-2, MMP-9, and PTH were independently associated with the risk of dental fluorosis (P&lt;0.05). Conclusions: High BALP, MMP-2, MMP-9, low OC, and PTH are independent factors affecting the occurrence of dental fluorosis and are related to the extent of dental fluorosis.

Biomarkers in Body Fluids as Indicators of Skeletal Maturity: A Systematic Review and Meta-analysis.

This review aimed to critically appraise the evidence for biomarkers in blood serum, gingival crevicular fluid (GCF), saliva, and urine in comparison with standard radiographic indices for skeletal maturation assessment. A thorough literature search in multiple databases was conducted for biomarkers in body fluids for skeletal maturation assessed with cervical vertebrae in lateral cephalograms or on hand-wrist radiographs. Different combinations including free text, MeSH terms, and Boolean operators were used. Two researchers used strict inclusion and exclusion criteria to screen title, abstract, and full text, and used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 instrument for risk of bias assessment of individual studies. Meta-analysis was performed on eligible studies using RevMan 5 software. A total of 344 articles were screened, of which 33 met the inclusion criteria and quality assessment. The skeletal maturity indicators included insulin-like growth factors (IGF-1), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP), dehydroepiandrosterone sulfate (DHEAS), vitamin D binding protein (DBP), parathormone-related protein (PTHrP), osteocalcin, metalloproteins, and serotransferrin (TF) along with different metabolites. At puberty, a significant rise was seen in IGF-1, DBP, ALP, osteocalcin, TF, and BALP. However, the serum DHEAS and PTHrP increased from pre-pubertal to post-pubertal stages. Due to the data heterogeneity, a meta-analysis could be performed on seven studies in total on IGF-1 in serum and blood. Of these, five were included for data in males and six in females, and four studies on IGF-1 in serum and blood. A significant difference in IGF-1 levels was seen between stages of peak pubertal growth spurt (CS3 and CS4) and decelerating pubertal growth (CS5) compared with growth initiation stage (CS2). Pubertal growth spurts were correlated with peak serum IGF-1 and BALP in both sexes individually. Peak ALP levels in GCF were correlated with the pubertal spurt in a combined sample of males and females. Standard biofluid collection protocols and homogeneity in sampling and methodology are strongly recommended for future research.

A Pilot, Open-Label, Proof-of-Concept Study To Evaluate the Efficacy and Safety of Asthiposhak® Tablets in Participants Suffering From Asthikshaya or Osteopenia.

Introduction Both osteoporosis and osteopenia are prevalent public health concerns worldwide and can lead to debilitating bone fractures. This study aimed to assess the efficacy of Asthiposhak® Tablets in individuals with Asthikshaya (osteopenia) by measuring changes in the bone mineral density (BMD) score before and after the intervention, specifically between visit 1 (baseline) and visit 8 (after 180 days of treatment). Methods The single-arm study involved the screening of participants for Asthikshaya (osteopenia) using baseline investigations, which included a bone mineral density (BMD) assessment through a dual-energy X-ray absorptiometry (DEXA) scan. A total of 36 participants were enrolled in the study, who took two Asthiposhak Tablets three times a day with lukewarm water, for a period of 180 days. Safety assessments, along with evaluations of BMD (DEXA Scan), Ayurvedic Symptom Score, and serum biochemical markers, were conducted through blood investigations. Efficacy and safety data were analyzed using 'intention-to-treat' analysis. Descriptive statistics were used to express data in percentages, mean ± SD, or median (IQR). Data at different intervals were compared using paired t-tests or Wilcoxon signed-rank tests. One-way analysis of variance (ANOVA) with Bonferroni correction tested the significance between visits for the Ayurvedic Symptom Score, and Friedman's two-way analysis of variance by ranks measured differences in vital parameters. The significance level used was p<0.05. Results Out of the initially recruited 36 participants, 30 successfully completed the study, consisting of 12 males and 18 females, with an age range of 40 to 70 years and a mean age of 51.33 years. After 180 days of treatment with AsthiposhakTablets, a statistically significant (p<0.05) improvement in hip and spine BMD (T-score) was observed. Additionally, significant reductions in the mean Total Ayurvedic Symptom Score were noted at both 90 and 180 days of treatment compared to day 0. Moreover, the levels of bone-specific alkaline phosphatase and osteocalcin, serum bone markers, showed statistically significant (p<0.05) reduction after 180 days of treatment compared to day 0. Importantly, all safety variables, including laboratory investigations, remained within the normal range following the 180-day treatment with Asthiposhak Tablets. Conclusion AsthiposhakTablets exhibited significant efficacy in enhancing both BMD (T-score) and Ayurvedic Symptom Score, thereby substantiating their osteoprotective potential in individuals with Asthikshaya (osteopenia). Furthermore, the tablets were found to reduce the levels of biochemical markers, such as serum bone-specific alkaline phosphatase and osteocalcin, suggesting their anti-resorptive action.

Denosumab biosimilar (LY01011) in the treatment of bone metastases in patients with solid tumors: A multicenter, randomized, double-blind, active comparator-controlled phase 3 study.

12126 Background: The study was to evaluate the equivalence of LY01011 to the reference product denosumab in terms of reduction of bone metabolism markers. Methods: Eligible patients were randomized at 1:1 ratio to receive 120 mg LY01011 injection or 120 mg denosumab every four weeks subcutaneously. Following the completion of three doses of 120 mg LY01011 or denosumab in a 12-week double-blind treatment period (DBTP), all enrolled patients would continue to receive LY01011 administration until the week 53 of follow-up period. The primary end point was the natural logarithm change at week 13 from baseline in urinary cross-linked N terminal telopeptide of type I collagen, corrected for urine creatinine (uNTx/uCr). The equivalence between LY01011 and denosumab would be concluded if the 90% CI was completely inside the pre-defined equivalence boundary between -0.135 and 0.135. A formal blinded sample-size re-estimation (BSSR) was planned to take place once 60% of the planned participants had completed the Week 13 assessments. After BSSR, the sample size increased from 560 to 850 according to prespecified procedure based on pooled standard deviationfrom the blinded data, which was set as a cap to ensure a feasible sample size for the study and no need to do any multiplicity adjustment. Results: All eligible 850 patients, included in the full analysis set, were randomized into the LY01011 group (n = 424) and denosumab group (n = 426). The samples from the 12-week DBTP were collected for analysis in both groups. The least square mean (LSM) (SE) of the natural logarithm change of uNTX/uCr at week 13 from baseline was -1.740 (0.0420) in the LY01011 group and -1.745 (0.0421) in denosumab group. The LSM difference was 0.005 between LY01011 and denosumab groups with 90% CI of [-0.088, 0.097] (p &gt; 0.05). Skeletal related events occurring in the LY01011 and denosumab groups were 3.5% and 2.8%, respectively. The mean (SD) percentage changes of serum bone-specific alkaline phosphatase (s-BALP) from baseline to week 13 were -31.154% (39.6790) and -33.021% (37.3826) in the LY01011 and denosumab groups, respectively. The median was -36.866% and -37.457% (p &gt; 0.05). The incidence of treatment-emergent adverse events (TEAEs) of any grade was 91.7% and 90.8% in LY01011 and denosumab groups(p &gt; 0.05). Both groups had 38.4% of Grade ≥3 TEAEs, of which 5.4% (LY01011) and 4.5% (denosumab) were judged to be related to the study drug. Immunogenicity analysis showed that no participant (0/399) had a positive ADA test in denosumab group and only one participant (0.2%, 1/401) was tested ADA positive in LY01011 group. Conclusions: The study demonstrated the equivalent efficacy of LY01011 in the reduction of bone metabolism biomarker NTX to reference product, denosumab, which met the primary endpoint. It had a good safety profile with no unexpected adverse reactions in the study. Clinical trial information: NCT04859569 .

Serum Bone-Specific Alkaline Phosphatase as an indicator of the quantity of callus formation in mandibular fracture patients seen in a Nigerian Teaching Hospital

It is important to evaluate the level of bone-specific alkaline phosphatase as it relates to the quantity of callus formed in mandibular fracture healing. The objective of the present study was to assess Serum Bone-Specific Alkaline Phosphatase (BsALP) as an indicator of callus formation in patients with mandibular fracture and determine the relationship between BsALP and callus formation using two treatment methods. Fifty-five patients with isolated mandibular fractures were enrolled. BsALP was measured at presentation, 3rd and 6th week. The patients were recruited into two treatment groups: Closed Reduction with Mandibulomaxillary Fixation (MMF) and Open Reduction and Internal Fixation (ORIF). The Callus Index was measured at 3rd and 6th week after treatment using digital postero-anterior view of the jaws on DICOM viewer software. The mean value of BsALP was 26.2±9.5 ng/mL. BsALP concentration in patients with double site fractures was higher than those with a single fracture, p=0.102. Peak serum BsALP observed in the 3rd week post-intervention was (28.1±8.2 ng/mL). Statistically significant differences were observed between the BsALP concentration in the 3rd and 6th week, and between BsALP concentration at presentation and 6th week, p&lt;0.001, respectively. There was no significant correlation between the Callus Index and mean serum BsALP at 6 weeks (r=-0.08, p=0.580). MMF treatment group had higher levels of serum BsALP compared with ORIF group in the 3rd week (p=0.14) and in the 6th week (p=0.18). BsALP is an indicator of the amount of callus formed in patients treated for mandibular fractures. Hence, it could be used as an adjunct to monitor the healing of mandibular fractures.

Association of follicle-stimulating hormone with bone turnover markers and bone mineral density in Chinese women across the menopausal transition.

Elevated follicle-stimulating hormone (FSH) is associated with an increased risk of postmenopausal osteoporosis. This study investigated the association of serum FSH with bone turnover markers (BTMs) and bone mineral density (BMD) in healthy women undergoing menopausal transition. A total of 487 healthy women (age 35-65 years, 50 ± 8.5 years) were enrolled in this study. Serum FSH, BTMs, and BMD at lumbar spine and total hip were measured in these subjects. Follicle-stimulating hormone was positively correlated with various BTMs (r = 0.339-0.583, all p < 0.001) and negatively correlated with lumbar spine and total hip BMD (r = -0.629 and -0.514, all p < 0.001). After adjusting for age and body mass index, the partial correlation coefficients of FSH with BTMs and BMD remained significant. Estimating from the regression equation, for every 10 IU/L increase in serum FSH, BTMs increased by 0.38-3.6 units, and BMD decreased by 0.03-0.05 g/cm2 , respectively. Multiple linear regression analysis showed that FSH was a positive factor for serum bone-specific alkaline phosphatase, osteocalcin, and N-telopeptide of collagen type 1 (β = 0.188-0.403, all p < 0.001), and a negative factor for lumbar spine BMD and serum C-telopeptide of collagen type 1 (β = -0.629 and -0.183, all p < 0.001). This study suggests that serum FSH levels are an independent risk factor for BTMs and BMD in menopause-transitioning women, particularly for serum BAP and lumbar spine BMD.

Prognostic value of alkaline phosphatase and bone-specific alkaline phosphatase in breast cancer: A systematic review and meta-analysis.

Numerous studies have reported the clinical value of alkaline phosphatase (ALP) and its bone-specific isoforms (bone-specific alkaline phosphatase (BAP)) in breast cancer. The purpose of this meta-analysis was to summarize the prognostic value of serum ALP and BAP in breast cancer, especially focused on bone metastasis and survival. PRISMA guidelines were followed to conduct this review. Observational studies were searched in PubMed, Cochcrane Library and EMBASE to January 1, 2022. Data were extracted to explore the prognostic value of ALP and BAP. The quality of the included studies was assessed and the outcome effects were evaluated. Subgroup and sensitivity analyses were performed to explore the potential sources of heterogeneity. Publication bias was assessed. There was a total of 53 studies with 22,436 patients included. For the primary outcome of survival, high levels of both ALP and BAP were associated with short survival time. The hazard ratio of high ALP level on overall survival was 1.72 (95% CI 1.37, 2.16, P < 0.001). For the secondary outcomes, a high ALP level (not BAP) was detected in breast cancer compared with healthy controls, and high levels of both ALP and BAP were risk factors for bone metastasis, while ALP (not BAP) was a risk factor for non-bone metastasis. This study showed that high levels of both serum ALP and BAP were associated with metastasis (BAP was associated with bone metastasis) and survival in breast cancer. The biomarkers could provide useful information for the early diagnostic assessment and monitoring in the follow-up of breast cancer patients.

Factors associated with osteoporosis and fractures in patients with systemic lupus erythematosus: Kyoto Lupus Cohort.

Osteoporosis and compression fractures of the lumbar spine are some of the major adverse effects of glucocorticoid therapy in patients with systemic lupus erythematosus (SLE). This study examined the association between bone mineral density, bone turnover markers, presence of vertebral fractures, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in SLE patients. This was a cross-sectional study of 246 outpatients with SLE at the Kyoto University Hospital. Lumbar and femoral bone mineral density was measured with dual-energy X-ray absorptiometry, and the presence of vertebral fractures was determined using X-ray, computed tomography, or magnetic resonance imaging. On multiple regression analysis, both high lumbar and femoral T-scores were associated with the concomitant use of hydroxychloroquine (P = .018 and P = .037, respectively), no use of bisphosphonate or denosumab (P = .004 and P = .038, respectively), high body mass index (P < .001), and low bone-specific alkaline phosphatase level (P = .014 and P = .002, respectively). Vertebral fractures showed a significant association with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score (P < .001) and femoral T-score (P < .001). Vertebral fracture was associated with SLE-associated organ damage, and serum bone-specific alkaline phosphatase level is a potentially useful marker for osteoporosis monitoring in SLE patients.

Dietary 25-hydroxycholecalciferol modulates gut microbiota and improves the growth, meat quality, and antioxidant status of growing-finishing pigs.

25-Hydroxycholecalciferol (25OHD3) is the active metabolite of regular vitamin D3 in vivo, which has a stronger biological activity and is more easily absorbed by the intestine than regular vitamin D3. Our study aimed to detect the potential influences of 25OHD3 on pork quality, antioxidant status, and intestinal microbiota of growing-finishing pigs receiving low-phosphorus (P) diet. Forty pigs [initial body weight (BW): 49.42 ± 4.01 kg] were allocated into two groups including low-P diet (CON group) and low-P diet supplemented with 50 μg/kg 25OHD3 (25OHD3 group). The whole experiment lasted for 88 days, including phase 1 (day 1-28), phase 2 (day 29-60), and phase 3 (day 61-88). The results showed that 25OHD3 supplementation tended to decrease feed conversion ratio in phase 3 and overall phase in comparison with the CON group. 25OHD3 increased (p < 0.05) serum contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased (p < 0.05) serum bone-specific alkaline phosphatase level. 25OHD3 increased (p < 0.05) mucosal GSH-Px activity in the duodenum and ileum, and tended to increase redness value and the activities of total antioxidant capacity and SOD in longissimus dorsi. 25OHD3 significantly upregulated the mRNA level of copper/zinc superoxide dismutase, and tended to change the mRNA levels of nuclear factor E2-related factor 2 and kelch-like ECH-associated protein 1 in longissimus dorsi. Moreover, 25OHD3 supplementation decreased (p < 0.05) n-6/n-3 and iodine value in longissimus dorsi. For bone quality, 25OHD3 supplementation increased (p < 0.05) calcium content, bone mineral content, and breaking strength in the metacarpal bones. Moreover, the colonic abundance of Lactobacillus was significantly higher in pigs fed with 25OHD3, and exhibited a positive association with serum antioxidant status, pork quality, and bone characteristics. Overall, the inclusion of 25OHD3 in low P diet partly improved production performance, meat quality, antioxidant capacity, bone properties, and gut microbiota composition of growing-finishing pigs.

Can Bone-Specific Alkaline Phosphatase be a Marker of Vascular Calcification in Type 2 Diabetes Mellitus?

Alkaline phosphatase (ALP) enzyme has been linked to vascular calcification. Unexplained elevations in serum ALP levels have been reported in patients with type 2 diabetes mellitus (T2DM). We assessed bone-specific alkaline phosphatase (BAP) levels in patients with T2DM who had unexplained ALP elevations and studied the association between BAP and other markers of vascular calcification. Patients with T2DM who had high serum ALP in the absence of known causes of ALP elevation were studied. The control group was T2DM patients with normal ALP. We measured the serum levels of BAP along with the leptin, fetuin-A, and vitamin K2 levels. Ankle-brachial index (ABI) was also measured in both groups. Serum BAP levels were significantly higher in the group with high ALP when compared with the normal ALP group. A significant positive correlation was present between BAP and serum fetuin-A as well as between BAP and Vit K2 levels. There was no correlation between BAP and serum leptin. ABI was comparable between the two groups. Patients with T2DM may have unexplained elevation in ALP due to an increase in BAP. Elevation in BAP may be associated with other markers of vascular calcification suggesting an increased risk of vascular calcification.

PTH Serum Levels and Mortality Risk among Incident Hemodialysis Patients

Introduction: Chronic kidney disease (CKD)-mineral and bone disorder (MBD) is a major complication in hemodialysis (HD) patients. Serum intact parathyroid hormone (iPTH) has been associated with prognosis in these patients, however, the optimal range to reduce mortality remains unknown. Methods: We conducted a retrospective study of incident HD patients, who were categorized into 4 groups according to iPTH serum level: &lt;150 pg/mL, 150-300 pg/mL, 301-600 pg/mL and &gt;600 pg/mL. All-cause and cardiovascular mortality over a mean follow-up of 3 years was assessed using standard survival methods. Results: One hundred and forty-nine patients were included. Patients with low iPTH presented low serum albumin, phosphorus, and bonespecific alkaline phosphatase (BAP), increased c-reactive protein (CRP) and higher serum bicarbonate (p&lt;0.05). Those with iPTH &lt;150 pg/mL had an increased risk of all-cause and cardiovascular mortality, when compared to those with iPTH 301-600 pg/mL (HR: 0.59; 95% CI: 0.36-0.96; p=0.035) and iPTH &gt;600 pg/mL (HR: 0.39; 95% CI: 0.20-0.78; p=0.008), even after adjusting for potential confounding factors as age, albumin, and comorbidities (diabetes, congestive heart failure (CHF), and hypertension). Discussion: PTH levels were associated with all-cause and cardiovascular mortality risk in our cohort of incident HD patients. Our results suggest that patients with low iPTH at HD initiation had an increased mortality risk, which may reflect a frail group of patients with anorexia, sarcopenia, malnutrition, and inflammation.

Effect of the Pulsed Electromagnetic Field Treatment in a Rat Model of Senile Osteoporosis In Vivo.

This study assessed the effects of pulsed electromagnetic fields (PEMF) in a rat model of senile osteoporosis and the underlying molecular events. 24-month-old male Sprague-Dawley (SD) rats were randomly divided into control and PEMF groups (n = 8 per group) using a random digit table, while 3-month-old male SD rats were set as the young-age control group. Rats in the PEMF group were treated by PEMF for 40 min/day for 5 days/week. Bone mineral density/microarchitecture, level of serum bone-specific alkaline phosphatase (BALP), tartrate-resistant acid phosphatase 5b (TRACP5b), and Wnt/β-catenin signaling genes in rat bone marrow cells were then analyzed. The 12-week PEMF intervention showed a significant effect on inhibition of age-induced bone density loss and deterioration of trabecular bone structures in the PEMF group rats versus control rats, that is, the treatment enhanced bone mineral density of the proximal femoral metaphysis and the fifth lumbar (L5) vertebral body and improved the proximal tibia and L4 vertebral body parameters using bone histomorphometry analysis. Furthermore, the BALP level in the bones was significantly increased, but the TRACP5b level was reduced in the PEMF group of rats versus control rats. PEMF also dramatically upregulated expression of Wnt3a, LRP5, β-catenin, and Runx2 but downregulated PPAR-γ expression in the aged rats. The results demonstrated that PEMF could prevent bone loss and architectural deterioration due to the improvement of bone marrow mesenchymal stromal cell differentiation and proliferation abilities and activating the Wnt signaling pathway. Future clinical studies are needed to validate these findings. © 2022 Bioelectromagnetics Society.

A multicenter, randomized, double-blind, phase III trial comparing denosumab biosimilar QL1206 and denosumab in patients with bone metastases from solid tumors.

2526 Background: This phase III study compared clinical efficacy, safety of the first biosimilar QL1206 with denosumab in solid tumor patients with bone metastases. Methods: Patients aged 18-80 years, with bone metastatic solid tumors and ECOG performance status of 0-2 were randomly assigned 1:1 to receive subcutaneous QL1206 or denosumab (120 mg Q4W, both) based on stratification factors (tumor types, previous skeletal-related event [SRE], and current systemic anti-tumor therapy). The primary efficacy endpoint was the percentage changes from baseline to week 13 in urinary N-telopeptide/creatinine ratio (uNTX/uCr); Clinical equivalence would be confirmed if the two-sided 90% confidence intervals (CI) of the least-squares mean (LSM) difference of natural log-transformed ratio of week 13 uNTX/uCr to baseline calculated by analysis of covariance were within the margins of ±0.135. The secondary endpoints included the percentage changes from baseline to week 25 and 53 in uNTX/uCr, the percentage changes from baseline to week 13, 25 and 53 in serum bone-specific alkaline phosphatase (s-BALP) and the time to on-study SRE. Adverse events (AE), immunogenicity (IG) and pharmacokinetics (PK) were also assessed. Population PK was analyzed using nonlinear mixed effects model. Results: 717 patients were randomized to the QL1206 (n = 357) and denosumab (n = 360) groups, respectively. The median percentage changes at week 13 in uNTX/uCr were -75.2% for QL1206 and -75.8% for denosumab. LSM of natural log-transformed ratio of week 13 uNTX/uCr to baseline were -1.429 (standard error 0.130) and -1.441 (0.130) in the two groups. The LSM difference between the two groups was 0.012 (90% CI -0.078 to 0.103; P = 0.8208), within the equivalence margins. Analyses for subgroups of sex, age, and randomization strata showed almost no significant differences. The secondary endpoints were also similar between the two groups (median percentage changes in s-BALP from baseline to week 13: -38.0% vs -37.1%; hazard ratio of time to SRE: 1.264 [95% CI 0.670 to 2.383]; both P &gt; 0.05). In the safety set, treatment-emergent AE occurred in 332 of 356 patients (93.3%) in the QL1206 group and 348 of 361 (96.4%) in the denosumab group. The proportions of positive anti-drug antibody (14/345 [4.1%] vs 16/352 [4.5%]), neutralizing antibody (three [0.9%], each), and PK characteristics were similar between the two groups. Conclusions: The results suggest that QL1206, the first biosimilar denosumab, is similar to denosumab with respect to clinical efficacy, acceptable safety, IG, and PK characteristics. The totality of evidence supports clinical equivalence of QL1206 and denosumab. Clinical trial information: NCT04550949.

The potential anti-osteoporotic effect of exercise-induced increased preptin level in ovariectomized rats.

Osteoporosis increases bone fragility and fractures. Preptin hormone is regulated by moderate exercise training and increases bone formation. Therefore, this study was conducted to see how estradiol administration and moderate exercise training affected osteoporotic changes in ovariectomized (OVX) rats. To achieve this aim, 36healthy adult female Wistar albino rats were randomized into Sham, OVX, ovariectomized estradiol-treated (OVX + E) (OVX + E rats were treated using subcutaneous estradiol benzoate 2.5μg/kg body weight/day), ovariectomized practicing moderate exercise training, ovariectomized estradiol-treated and practiced a moderate exercise training, and ovariectomized alendronate-treated (OVX + Alen) (OVX + Alen rats were treated orally with alendronate 3mg/kg body weight/week) groups. Alendronate was used as a standard anti-osteoporotic drug. Moderate exercise training, including therapy with estradiol and alendronate for OVX rats began on the fourth week and lasted for six weeks. Results showed that OVX rats had estrogen and preptin deficiency in serum. These deficiencies were associated with a significant increase in bone resorption biomarkers (urinary deoxypyridinoline and hydroxyproline), and bone formation biomarkers (serum osteocalcin and bone-specific alkaline phosphatase). Also, serum pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-6) were increased, while bone osteopontin (OPN) expression was decreased. Subsequently, the osteoporotic alterations were verified based on histopathological changes. From the results, estradiol therapy and moderate exercise training significantly improved these findings to the same extent as that of the standard alendronate treatment. Therefore, through their anti-inflammatory properties, increasing bone OPN expression, and regulating serum preptin; estradiol therapy and moderate exercise training can reduce osteoporotic alterations in OVX rats. Thus, combined estradiol therapy and moderate exercise training could be a promising potential therapeutic protocol to reduce postmenopausal osteoporosis. Also, targeting serum preptin and bone osteopontin regulation could have a critical role in the treatment of postmenopausal osteoporosis.

Randomized Double-Blind Comparative Study of First Global Denosumab Biosimilar in Oncology

Abstract Purpose The aim of this study was to compare first global biosimilar denosumab for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. Methods It was a randomized, double-blind, comparative clinical study. Total of 136 patients of solid tumor were dosed (i.e., 102 subjects in study arm and 34 subjects in the reference arm) with initial double-blind period of 24 weeks (primary efficacy) followed by open-label phase till week 36. Primary endpoint was the incidence of first on-study SRE including hypercalcemia of malignancy with co-primary endpoint of median time to first on-study SRE. Secondary endpoints included mean number and time to first and subsequent on-study SREs (week 12, 24, 36), incidence/proportion of patients with first and subsequent on-study SREs (week 24, 36), change from baseline in nuclear bone scan, quality of life assessment, pharmacokinetics, pharmacodynamic, and safety. Results In biosimilar study arm, 06 (5.83%) patients suffered SRE from baseline to week 24 compared with 02 (5.71%) patients in reference arm with one (0.97%) patient showing pathological fracture in study arm and one (2.86%) patient having spinal cord compression in reference arm. There was no statistically significant difference in median time to first SRE, mean number of SRE/patient in both arms and improvement in bone repair on nuclear scan at 12, 24 and 36 weeks. Though the study arm showed better health-related quality of life (HRQoL), mean change in HRQoL was statistically not different in both the arms. Pharmacodynamics, serum bone-specific alkaline phosphatase, pharmacokinetic and safety evaluation did not show any statistical difference between arms. Conclusion There was no clinically meaningful difference in the biosimilar denosumab and reference product after detailed efficacy and safety evaluation.

Telmisartan: An angiotensin receptor blocker regulates osteoclastogenesis via inhibition of the ERK triggering in osteoporotic male rats.

Great attention was recently given to the importance of RAS in controlling inflammatory bone diseases, following the discovery of its local existence in skeletal tissues. Local RAS was found to be expressed on osteoblastic and osteoclastic cells and to exert its action via angiotensin II (AngII) receptors, including angiotensin II type 1 receptor (AT1 R) and angiotensin II type 2 receptors. Telmisartan (TLM), an AT1 R blocker (ARBs), was investigated in the present study for its therapeutic effect on bone health in osteoporotic rats. d-Galactose, a reducing sugar at a dose of 200 mg/kg/day/i.p., was used to induce osteoporosis in male rats. TLM, at a dose of 5mg/kg/day, was orally introduced in the osteoporotic rats for four consecutive weeks. Tibia and femur bone densitometry was estimated, bone formation and bone resorption biomarkers serum levels were measured, mineral content in blood was also valued, and finally the extracellular regulated kinase (ERK) expression in bone was determined. TLM considerably improved the deleterious effect of d-galactose on bone mineral density. It blunted serum bone-specific alkaline phosphatase and osteocalcin while elevating serum osteoprotegrin (OPG). On the other hand, TLM turned off the pronounced elevation in serum receptor activator of nuclear factor-κβ ligand (RANKL), tartrate-resistant acid phosphatase, and cathepsin K. Furthermore, it significantly hindered the bone expression of ERK which hampered osteoclastogenesis. AT1 R inhibition abolished the rise in serum calcium and phosphorus and normalized serum superoxide dismutase and catalase. These TLM protective effects in d-galactose-treated rats were confirmed by the histopathological examination. The results all together denote the potential therapeutic value of ARBs therapy in osteoporosis.