Tartrate-resistant Acid Phosphatase 5b Research Articles

#2034 CKD-MBD management: results from a national survey on bone turnover biomarkers practice and therapeutic strategies among Italian nephrologists

Abstract Background and Aims Advanced stages of chronic kidney disease (CKD) are constantly characterized by a mineral and bone disorders (MBD) syndrome concerning a complex systemic condition that includes laboratory abnormalities of bone and mineral metabolism involving calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; abnormalities in bone turnover, mineralization, volume, or strength; extra-skeletal calcifications, such as vascular or other soft tissue. CKD-MBD syndrome determines relevant consequences in terms of fragility fractures, cardiovascular events and higher mortality. The nephrologist's awareness of CKD-MBD diagnostic and management tools and therapeutic strategies is key to improving CKD patients’ prognosis and outcomes. Method A new national survey (composed of 17 online questions) was conducted among Italian nephrologists to investigate the reference laboratory availability of bone turnover markers (BTMs), the clinical attitude on secondary hyperparathyroidism (sHPT) management, and the CKD-MBD therapeutic approach in different stages of CKD and dialysis patients. Results 89 Italian nephrologists participated in the survey. The reference laboratories largely fulfill the biomarkers request of ionized calcium (97.7%), phosphorus (100%), PTH (100%), alkaline phosphatase (ALP) (100%), magnesium (100%), 25-OH and 1,25-OH vitamin D levels (92.1%; 53.9%); while most of the hospital laboratories do not regularly support the availability of specific BTMs, both for diagnosis and monitoring the bone resorption and formation (Fig. 1)—such as bone ALP (75.3%), calcifediol (37.1%), calcitriol (40.5%), fibroblast growth factor-23 (FGF-23) (intact 9% and c-terminal 4.5%), vitamin K (33.7%), Klotho (6.75%, soluble 4.5%), osteocalcin (38.2%), matrix gla protein (10.1%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (6.75%), cross-linked collagen type I peptide (CTX) (32.6%) and procollagen type 1 n-terminal propeptide (P1NP) (10.1%). The nephrologist's attitude to start management and treatment of sHPT is revealed to be mainly led by KDOQI (n = 42, 47%) and KDIGO (n = 39, 44%) guidelines considering their PTH cut-off values; in 53.9% of clinicians the measure of PTH levels is then performed every 3 months according to KDOQI guidelines. In relation to the definition of high turnover metabolic bone disease by BTMs, this metabolic pattern is identified in > 50% and 30-40% of patients with CKD 4-5D by 31.5% and 21.4% of nephrologists, respectively. 65% of clinicians currently considered ALP of equal importance as alterations of PTH as a predictor of fracture events. Other biomarkers, such as FGF-23, P1NP or TRAP-5b, emerge to not be still used in regular clinical practice. In patients diagnosed with CKD-MBD and skeletal fragility, 76.4% of nephrologists consider the AIFA (Italian Medicines Agency) note 79 to support osteoporosis treatment. The therapeutic strategies of CKD-MBD include the administration of vitamin D (e.g. cholecalciferol 27-37.1%, calcifediol 9-12.4%, calcitriol 42.7-55.1%) and its analogues (e.g. paricalcitol 23.6-52.8%) and the use of antiresorptive agents (e.g. alendronate 3.4%-23.6%, denosumab 22.5%-30.3%) with variable frequencies among different advanced CKD stages and for those patients on peritoneal or hemodialysis (Fig. 2). Conclusion Results present a suboptimal use of BTMs and a current heterogeneous therapeutic management of CKD-MBD syndrome and renal osteodystrophy in Italian clinical practice. The survey represents a starting point of work to further implement awareness of diagnostic and therapeutic issues of CKD-MBD.

#2708 Impact of dialysis modality on bone phenotype

Abstract Background and Aims Literature data suggest that low bone turnover is the prevailing bone phenotype in patients treated with peritoneal dialysis (PD) and point to high sclerostin as the central culprit. Lack of adequate controls, diagnostic heterogeneity, and a changing mineral metabolism landscape and armamentarium call for a cautious interpretation and confirmation in contemporary patients. Method Laboratory parameters of mineral metabolism (biointact parathyroid hormone (PTH), fibroblast growth factor 23 [FGF23] and sclerostin), bone turnover markers (bone alkaline phosphatase [BALP], intact procollagen type I N-terminal propeptide [PINP], tartrate-resistant acid phosphatase 5b [TRAP5b]) and bone mineral density (BMD) were assessed in 636 non-diabetic kidney transplant candidates of whom 447 were treated with hemodialysis (HD) and 189 with PD. A bone biopsy was performed in 204 patients (n = 134 HD; n = 70 PD), with bone sclerostin expression assessed in a subset (n = 52). Results Patients treated with PD had lower levels of PINP (79.6 vs 99.5 ug/L; p < 0.01) and BALP (20.2 vs 23.7 ug/L; p = 0.04) compared to those treated with HD. Histomorphometric parameters of bone formation were numerically lower in patients treated with PD, but significance was not reached. Bone mineralization was impaired in HD patients (osteoid width: 7.90 vs 6.75 µM; p = 0.01; osteoid maturation: 9 vs 6 days; p = 0.03), while frank osteomalacia was rare in both modalities (6.0%, both groups). BMD was higher in patients treated with PD compared to HD at skeletal sites rich in cortical bone (Z-score midshaft radius −0.4 ± 1.3 vs −0.9 ± 1.7; p = 0.04). PTH levels were comparable (150 vs 144 pg/mL, PD vs HD), while patients treated with PD showed higher serum phosphate (4.9 ± 1.3 vs 4.5 ± 1.6 mg/dl; p < 0.01) and FGF23 levels (3852 pg/ml vs 2361 pg/ml; p = 0.01). Circulating (1.82 ng/mL, both groups) and bone tissue expression (205 ± 126 vs 206 ± 112 positive osteocytes per mm2) of sclerostin did not differ between groups. Conclusion Patients treated with PD present a lower bone turnover, better mineralization, and higher cortical BMD than counterparts treated HD. Overall, differences are marginal and most probably clinically irrelevant. We speculate that inferior phosphate control may be in the causal pathway.

#492 Ten-year experience treating osteoporosis with bisphosphonate in hemodialysis patients

Abstract Background and Aims The treatment of osteoporosis in patients undergoing hemodialysis (HD) has not been established, as there is insufficient evidence regarding the treatment of osteoporosis. The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 guidelines suggest that determining the bone marrow density (BMD) of HD patients is useful. In 2011, we began treating HD patients' osteoporosis with alendronate. Herein, we describe the effects of the treatment based on our 10-year experience. Method This was a single-center prospective observational study of 85 HD patients (age 67.8 ± 11.0 yrs; 47 females, 38 males) treated for osteoporosis with alendronate at our hospital during the 10 years 2011–2021. The average observational period was 3.9 ± 2.9 years. The patients' BMD values including those at the lumbar spine, femoral neck, and total hip were determined by dual-energy X-ray absorptiometry. The patients whose first T-score was ≤ −2.5 were treated with alendronate. We evaluated the patients' yearly BMD measurements and their yearly values of bone metabolism markers, i.e., parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase 5b (TRACP-5b). Results We compared the data before and after the start of alendronate treatment by dividing the patients into a responder group (the patients whose T-score had improved at 1 year after treatment started; n=44) and a non-responder group (the patients whose T-score had not improved; n=32). The mean observational period of the responder group was significantly longer than that of the non-responder group (p<0.01). In a multiple regression analysis, a longer observational period was significantly associated with the improvement of T-scores (p=0.02). Only the mean T-score of the lumbar spine gradually improved during the study period; those of the femoral neck and total hip did not. Conclusion A long-term use of alendronate for the treatment of osteoporosis may be effective in hemodialysis patients, especially for the lumbar spine. Decisions regarding the effect of alendronate treatment for osteoporosis patients undergoing HD should not be made within only a year after the treatment initiation; rather, a longer observation period is necessary.

#1443 Bone and mineral metabolism in patients with nephropathic cystinosis as a function of age and eGFR

Abstract Background and Aims Cystinosis-associated metabolic bone disease (CMBD) is a major challenge in the treatment of patients with infantile nephropathic cystinosis (NC). Study data are limited due to small case numbers, lack of adults or patients on renal replacement therapy and/or inadequate assessment of bone health. Method We investigated markers for CMBD in all age groups (1-44 years; 61% children) and CKD stages 1-5D/T in the largest NC cohort to date with 103 German and Austrian NC patients. Skeletal comorbidity and concentrations of fibroblast growth factor 23 (FGF23), the osteoblast marker bone-specific alkaline phosphatase (BAP), the bone remodeling inhibitor sclerostin, the osteoclast marker tartrate-resistant acid phosphatase 5b (TRAP5b), the soluble receptor activator of nuclear factor kappa B ligand (sRANKL), osteoprotegerin (OPG) and the sRANKL/OPG ratio as surrogates for the regulation of osteoclastogenesis by osteoblasts were determined by ELISA, converted into age- and sex-specific z-scores and compared as a function of eGFR. Multivariable regression analyses were used to identify specific influencing factors associated with biochemical and clinical findings in pre-transplant NC patients. Results Skeletal complications occurred in two-thirds of patients, with the risk being five times higher in adults than in children. Pediatric and adult NC patients with CKD stages 1-4 showed hypophosphatemia and hypocalcemia associated with suppressed FGF23 and PTH levels and elevated BAP concentrations. This was associated with age, eGFR and treatment with phosphate and active vitamin D, suggesting more vigorous treatment of Fanconi syndrome in pre-transplant patients. As indicated by the increased TRAP5b and decreased sRANKL/OPG ratio, osteoclast activity was increased despite counterregulation by osteoblasts, which in conjunction with increased sclerostin activity may have contributed to the progressive bone loss and skeletal comorbidity in our patient cohort. Conclusion Bone health in NC progressively deteriorates with age, largely due to persistent rickets/osteomalacia associated with inadequate treatment of Fanconi syndrome and increased osteoclast activity despite osteoblast counterregulation via OPG/RANKL. Our data suggest that a primary osteoclast defect in NC promotes increased bone resorption, limiting maximal bone mass and leading to progressive bone loss and increased skeletal comorbidity.

#3127 Bedside cycling modulated the bone-resorption markers in patients with end-stage renal disease

Abstract Background and Aims Exercise provided multifactorial benefits in improving the health of the CKD patients. The exercise itself improved the bone remodeling. For CKD patients, chronic kidney disease mineral bone disorder (CKD-MBD) is an important complication and the treatment for renal osteodystrophy is unsatisfactory. The aim of study is to validate the role of bedside cycling in bone remodeling markers for patients with end-stage renal disease (ESRD). Method Participants were grouped into 4 groups: health control, chronic kidney disease (GFR 15∼60 ml/min) and ESRD (GFR<15 ml/min with maintenance dialysis). For ESRD patients, 12-week bedside cycling ((30 minutes per session; 3 times per week) were given for subjects. The pre-and post-exercise bone remodeling markers and clinical outcome were compared in ESRD with and without exercise in ESRD subjects. Results Bone formation markers (Bone specific alkaline phosphatase (15.57 ± 1.59 pg/dL) and Procollagen type 1 amino-terminal propeptide (1269.12 ± 116.34 pg/dL) were higher in ESRD patients with correlation with indoxyl sulfate and intact parathyroid hormone concentration(p < 0.05) respectively. In ESRD patients, the post-exercise concentration of Tartrate-resistant acid phosphatase 5b (3.64 ± 0.25 pg/dL to 4.23 ± 0.31 pg/mL, p = 0.003) and N-terminal telopeptide-1 (113.67 ± 20.53 pg/mL to 260.61 ± 30.9 pg/mL, p = 0.001)increased after 12 weeks of bed-side cycling. The hospitalization and mortality were similar between ESRD with or without exercise. Conclusion The bone formation marker concentration increased along with the severity of CKD. Bedside cycling increased the concentration of the bone resorption markers in ESRD patients.

Impact of pheochromocytoma or paraganglioma on bone metabolism: A systemic review and meta-analysis

Preclinical and animal studies have suggested that excess catecholamines can lead to bone mineral loss. However, to date, no systematic review is available that has analyzed the impact of catecholamine excess in the context of pheochromocytoma/paraganglioma (PPGL) on bone metabolism. We conducted this meta-analysis to address this knowledge gap. Electronic databases were searched for studies evaluating bone metabolism, including assessments of bone mineral density (BMD), quantitative computed tomography (qCT), trabecular bone score (TBS), or bone turnover markers in patients with PPGL. These markers included those of bone resorption, such as tartrate-resistant acid phosphatase 5b (TRACP-5b) and cross-linked C-telopeptide of type I collagen (CTx), as well as markers of bone formation, such as bone-specific alkaline phosphatase (BS ALP). Out of the initially screened 1614 articles, data from six studies published in four different patient cohorts with PPGL that met all criteria were analysed. Individuals with PPGL had significantly lower TBS [Mean Difference (MD) -0.04 (95% CI: -0.05--0.03); p < 0.00001; I2 = 0%], higher serum CTx [MD 0.13 ng/ml (95% CI: 0.08-0.17); p < 0.00001; I2 = 0%], and higher BS-ALP [MD 1.47 U/L (95% CI: 0.30-2.64); p = 0.01; I2 = 1%]. TBS at 4-7 months post-surgery was significantly higher compared to baseline [MD 0.05 (95% CI: 0.02-0.07); p < 0.0001]. A decrease in CTx has been documented post-surgery. Bone health deterioration is a major concern in patients with PPGL. In addition to providing a definitive cure for catecholamine excess, monitoring and treating osteoporosis is essential for individuals with secondary osteoporosis due to PPGL. Long-term studies on bone health outcomes in PPGL are warranted.

The Impact of a 6-Week Nordic Walking Training Cycle and a 14-Hour Intermittent Fasting on Disease Activity Markers and Serum Levels of Wnt Pathway-Associated Proteins in Patients with Multiple Myeloma.

Background: Multiple myeloma (MM) accounts for about 10-15% of all diagnosed hematologic malignancies and about 1-2% of all cancer cases. Approximately 80-90% of MM patients develop bone disease and the changes rarely regress. It is only possible to stop or slow their progression. A major role in bone destruction in MM is attributed to the Wnt signaling pathway, and its action can be modified by various types of interventions including training and diet. Therefore, the aim of this project was to evaluate the effects of a Nordic Walking (NW) training cycle and intermittent fasting (IF) on the levels of selected bone turnover markers associated with the Wnt pathway in patients with MM. Materials and methods: Results from 35 patients divided into training (NW and IF NW) and non-training (IF and control) groups were included in the analysis. A 6-week training cycle involving 60 min workouts 3 times a week was conducted. Body mass and composition as well as the levels of vitamin D, calcium and phosphorus, beta2-microglobulin, and albumin were examined before and after the completion of the training cycle. Markers of bone turnover were also determined: sclerostin (SOST), Dickkopf-related protein 1 (DKK-1), osteoprotegrin (OPG), osteopontin (OPN), and Tartrate-resistant acid phosphatase 5b (TRACP 5b). Results: There was no negative effect of IF or combined training and fasting on the nutritional status of the patients (the level of albumins was unchanged). Both training groups showed an increase in serum concentrations of the active metabolite of vitamin D (IF NW and NW: p = 0.001 and p = 0.022, respectively). The change in the concentration of this vitamin negatively correlated with the concentration of TRACP 5b (r = -0.413, p = 0.014). Evaluating the concentrations of markers related to bone turnover, a reduction in the concentrations of SOST (time: p = 0.026, time vs. group: p = 0.033) and TRACP 5b (time: p < 0.001, time vs. group p < 0.001) was indicated. Conclusions: The obtained results allow one to indicate the training with the poles as a safe and beneficial form of physical activity that should be recommended to patients suffering from MM. However, the results obtained in the present study are not sufficient to show the beneficial effect of IF applied without trainings.

Abstract PS16-04: Denosumab as an enhancer of the immune infiltrate in hormone receptor-positive early breast cancer. Subgroup analysis from the D-Biomark window-of-opportunity clinical trial (NCT03691311)

Abstract Background: The receptor activator of nuclear factor κB (RANK) signaling pathway has emerged as a therapeutic target in breast cancer (BC). Recent studies indicate that inhibition of the RANK pathway induces tumor cell differentiation and may enhance the anti-tumor immune response. The D-Biomark clinical trial aims to evaluate the antitumor (antiproliferative and proapoptotic) and immunomodulatory effects of denosumab in HER2-negative early BC. Methods: Patients with early HER2-negative BC scheduled for primary surgery were randomized in a 2:1 ratio to receive two doses of 120 mg denosumab on days 1 and 8 vs no treatment before surgery. Immunohistochemistry (IHC) was used to assess Ki67 (proliferation), cleaved caspase-3 (cell survival), RANK and RANKL. Stromal tumor infiltrating lymphocytes (TILs) and serum markers including free RANKL (sRANKL), tartrate-resistant acid phosphatase 5b (TRACP5b), and osteoprotegerin (OPG) were also analyzed. Paired t-test was used to compare values between core biopsy (biopsy A) and surgical samples (biopsy B). Subgroup analysis by intrinsic subtype was performed on 47 matched cases using PAM50. Results: Between July 2019 and May 2021, we enrolled 60 patients, 58 evaluable, including 10 triple-negative breast cancer (TNBC). The clinicopathologic characteristics of the population at the time of enrollment were well balanced, but the TNBC recruited included 5 out of 10 tumors with a more indolent behavior than the typical tumors of this lineage (apocrine tumors, low cell proliferation). Due to this and the small number of cases, no conclusions can be drawn in this subgroup. RANK expression was detected in 19 tumor cases, while 17 cases expressed RANKL. The treated group showed a decrease in sRANKL (p &amp;lt; 0.000), indicating denosumab activity, while the control group showed no change (p1.0). OPG levels in the experimental group showed a non-significant increase (p0.07), while TRACP5b remained unchanged. Both groups showed a non-clinically relevant increase in cell proliferation (5 percentage points), control p0.04, experimental p0.01. Subgroup analysis of tumors with RANK+ or RANKL+ tumor cells also showed no reduction in Ki67. Cell survival did not decrease in the overall cohort (control p0.05, experimental p0.24), nor in subgroups or in tumors with RANK+ or RANKL+ tumor cells. Denosumab treatment increased TILs in the overall population (control p0.06, experimental p0.0006) and in the subgroups: RANK+ tumors, RANKL+ tumors, premenopausal and postmenopausal, less so in the TNBC group. The subgroup analysis is shown in Table 1. Analysis by intrinsic subtype showed that in the experimental group there was an increase in cases with a change to luminal A lineage (17%) compared to the control group (6%), suggesting a possible cellular differentiation towards less aggressive tumors. Although the number of patients is small, these changes warrant further investigation and highlight the role of denosumab as an immune activator in these luminal tumors known for their low inflammatory infiltrate. Conclusion: Two doses of denosumab prior to surgery did not reduce proliferation or increase apoptosis. However, this short course of denosumab increased TILs in early BC, particularly in luminal tumors, and may induce tumor cell differentiation into luminal A-like tumors. Table. Citation Format: Andrea Vethencourt, Eva Trinidad, Eduard Dorca, Anna Petit, Teresa Soler-Monsó, Agostina Stradella, Cristina Capo, Ander Urriticoechea, Marta Matas, Gema Pérez-Chacon, María Jimenez, Marina Ciscar, Emilia Brizzi, Gonzalo Soria Alcaide, Gonzalo Gomez, Elena Piñeiro, Elvira Purqueras, Amparo Garcia, Ariadna Iserte, M Jesus Pla, Miriam Campos, Miguel Gil-Gil, Sonia Pernas, Eva Gonzalez-Suarez, Catalina Falo. Denosumab as an enhancer of the immune infiltrate in hormone receptor-positive early breast cancer. Subgroup analysis from the D-Biomark window-of-opportunity clinical trial (NCT03691311) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-04.

Role of Leptin in Regulating Renal Phosphate Transport

Elevated plasma phosphate (Pi) levels, known as hyperphosphatemia, are associated with an increased risk of cardiovascular complications and mortality. Although studies have suggested a correlation between obesity and hyperphosphatemia/phosphate toxicity, the root cause of this observation has not been established. Since hyperleptinemia was also found to be associated with abnormalities in bone structure, we hypothesized that effects on renal Pi transport are responsible for this observation. To address this question, we studied hyperleptinemic mice (db/db, n=14) and compared them to wild-type mice (WT, n=10). Blood and urine samples, as well as kidney tissues, were collected and analyzed. Body weight was approximately twice as high in db/db compared to WT mice (59±3 vs. 30±2 g, P&lt;0.05). Plasma Pi levels in db/db mice were significantly greater (~1.5-fold) compared to WT mice (2.6±0.1 vs. 1.7±0.1 mmol/L, P&lt;0.05). However, urinary Pi /creatinine ratios were similar between genotypes. Plasma Ca2+ levels in db/db mice were significantly higher compared to WT mice (2.68±0.03 vs. 2.48±0.03 mmol/L, P&lt;0.05) alongside urinary Ca2+/creatinine ratios being significantly higher in db/db mice compared to WT mice (1.6±0.4 vs. 0.3±0.1 mmol/mmol, P&lt;0.05). Plasma parathyroid hormone (PTH, regulating Pi and Ca2+) levels were similar in both genotypes. The phosphaturic hormone fibroblast growth factor 23 (FGF23), which is produced and released from bone, was slightly but significantly elevated in db/db compared to WT mice (254±12 vs. 227±18 pg/mL, P&lt;0.05). Bone formation markers (osteocalcin and procollagen type I N-propeptide) and bone resorption markers (tartrate-resistant acid phosphatase 5b and C-terminal telopeptide of type I collagen) were similar between genotypes, indicating that Pi and Ca2+ release from bone may not be causing these mineral differences. To determine the role of the kidney for the development of hyperphosphatemia, we performed 32P radiotracer studies in acutely isolated renal brush border membrane vesicles. Sodium-dependent 32P transport was not significantly different between genotypes. To determine the ambient in vivo contribution of the Na+-Pi cotransporter Npt2a, we employed acute pharmacological inhibition with PF-06869206 (Npt2a inhibitor, 30 mg/kg b.w, n=7) or vehicle (n=11) and compared plasma Pi before and 2 hours after administration in db/db mice. Vehicle treatment slightly increased plasma Pi levels compared to baseline (2.6±0.1 vs. 2.1±0.1 mmol/L, P&lt;0.05); in contrast, the Npt2a inhibitor significantly reduced (~50%) plasma Pi levels compared to baseline (1.3±0.1 vs. 2.5±0.1 mmol/L, P&lt;0.05). In summary, our study demonstrates that hyperphosphatemia in db/db mice is not caused by changes in renal Pi transport or bone turnover, suggesting that possibly intestinal mechanisms are responsible for increased Pi, and possibly Ca2+, absorption. Of note, Npt2a inhibition was effective in reducing hyperphosphatemia in db/db mice, indicating a potential therapeutic strategy. This work was supported by a VA Merit Review Award IBX004968A (to Dr. Rieg) and a Pilot Project from the USF Microbiomes Institute (to T.R. and J.D.R). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Calcium-fortified fresh milk ameliorates postmenopausal osteoporosis via regulation of bone metabolism and gut microbiota in ovariectomized rats

The aging of the global population has made postmenopausal osteoporosis prevention essential; however, pharmacological treatments are limited. Herein, we evaluate the effect of calcium-fortified fresh milk (FM) in ameliorating postmenopausal osteoporosis in a rat model established using bilateral ovariectomy. After 3 months of FM (containing vitamin D, and casein phosphopeptides, 1000 mg Ca/100 g) or control milk (110 mg Ca/100 g milk) supplementation, bone changes were assessed using dual-energy X-ray absorptiometry, microcomputed tomography, and bone biomechanical testing. The results revealed that FM can regulate bone metabolism and gut microbiota composition, which act on bone metabolism through pathways associated with steroid hormone biosynthesis, relaxin signaling, serotonergic synapse, and unsaturated fatty acid biosynthesis. Furthermore, FM administration significantly increased bone mineral content and density in the lumbar spine and femur, as well as femoral compressive strength, while improving femoral trabecular bone parameters and microarchitecture. Mechanistically, we found that the effects may be due to increased levels of estrogen, bone formation marker osteocalcin, and procollagen type I N-propeptide, and decreased expression of the bone resorption marker C-telopeptide and tartrate-resistant acid phosphatase 5b. Overall, the findings suggest that FM is a potential alternative therapeutic option for ameliorating postmenopausal osteoporosis.

Dairy consumption, bone turnover biomarkers, and osteo sono assessment index in Japanese adults: A cross-sectional analysis of data from the Iwaki Health Promotion Project

PurposeDairy foods are nutritional sources of calcium, phosphorus, protein, and other nutrients that improve bone health. However, the effects of dairy consumption on bone biomarkers in the Japanese population remain unclear. This study explored the association between dairy consumption and bone biomarkers in Japanese adults. MethodsThis cross-sectional study was conducted as part of the Iwaki Health Promotion Project in Aomori, Japan. In total, 1063 adults were included in the analysis. Bone turnover marker levels were measured in local citizens during their annual medical checkups. The calcaneus osteo sono assessment index (OSI) was calculated using a quantitative ultrasound technique. The dietary intake of foods and nutrients was estimated using a food frequency questionnaire. Linear regression models were established using dairy consumption and bone biomarkers with adjustments. Statistic significance was considered by P < 0.05. ResultsIn multivariate models, the tartrate-resistant acid phosphatase 5b and parathyroid hormone concentrations were inversely associated with dietary dairy consumption after adjusting for age and sex. The undercarboxylated osteocalcin, a procollagen type I N-terminal peptide to bone alkaline phosphatase ratio, and OSI were the directly associated with dairy consumption in multivariate models with adjustment. ConclusionsDairy consumption is partially associated with bone turnover biomarkers and OSI in adult Japanese participants. Habitual consumption of dairy foods may contribute to the nutritional supplementation for maintaining bone health, including turnover and structure. Clinical trial registry number and website where it was obtainedThe Japanese Clinical Trials Registry (UMIN000040459), https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000046175.

Clinical Efficacy of Bisphosphonates in Treating Osteoporosis in Diabetes Patients: A Meta-Analysis.

The aim of the study was to explore the clinical efficacy of bisphosphonates in patients with osteoporosis in diabetes patients by meta-analysis. Six databases were systematically searched from inception to January 30,2023. Studies evaluating the treatment of diabetic osteoporosis with bisphosphonates were included. Key outcome measures, such as bone mineral density (BMD), bone metabolism markers, pain improvement, and safety assessments, were extracted and analyzed. STATA MP V17.0 was used to calculate the combined effect size. After searching Chinese and English databases, 15 studies met the inclusion criteria of this study. The results of the meta-analysis showed that the BMD of patients with osteoporosis in diabetes increased significantly after bisphosphonate treatment, and the lumbar BMD increased by 0.08 g/cm² (95% CI: 0.05-0.11). Femoral neck BMD increased by 0.06 g/cm² (95% CI: 0.01-0.11); Ward's triangle BMD increased 0.07 g/cm² (95% CI: 0.04-0.09); and trochanter BMD increased by 0.06 g/cm² (95% CI: 0.04-0.08). In addition, bone alkaline phosphatase increased 1.95 μg/l (95% CI: 1.18-2.72), while serum tartrate-resistant acid phosphatase-5b decreased 1.28 U/l (95% CI: -1.81-0.75). Moreover, improvements in pain were statistically significant. The effects of bisphosphonates on osteocalcin (MD: -0.07; 95% CI: -1.12-1.25), serum calcium (MD: 0.01; 95% CI: -0.03-0.04), serum phosphorus (MD: 0.04; 95% CI: -0.03-0.10) and medication safety (OR: 1.75; 95% CI: 1.29-2.37) were not statistically significant. Bisphosphonates have a significant positive effect on bone mineral density and bone metabolism in patients with osteoporosis in diabetes and have good safety.

Effects of sodium-glucose cotransporter 2 inhibitors on bone metabolism in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

BackgroundSodium glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes mellitus (T2DM) therapy. The impact of SGLT2 inhibitors on bone metabolism has been widely taken into consideration. But there are controversial results in the study on the effect of SGLT2 inhibitors on bone metabolism in patients with T2DM. Therefore, we aimed to examine whether and to what extent SGLT2 inhibitors affect bone metabolism in patients with T2DM.MethodsA literature search of randomized controlled trials (RCTs) was conducted through PubMed, Web of Science, Embase, Cochrane databases, and Scopus from inception until 15 April 2023. Eligible RCTs compared the effects of SGLT2 inhibitors versus placebo on bone mineral density and bone metabolism in patients with T2DM. To evaluate the differences between groups, a meta-analysis was conducted using the random effects inverse-variance model by utilizing standardized mean differences (SMD).ResultsThrough screening, 25 articles were finally included, covering 22,828 patients. The results showed that, compared with placebo, SGLT2 inhibitors significantly increased parathyroid hormone (PTH, SMD = 0.13; 95%CI: 0.06, 0.20), and cross-linked C-terminal telopeptides of type I collagen (CTX, SMD = 0.11; 95%CI: 0.01, 0.21) in patients with T2DM, decreased serum alkaline phosphatase levels (ALP, SMD = -0.06; 95%CI: -0.10, -0.03), and had no significant effect on bone mineral density (BMD), procollagen type 1 N-terminal propeptide (P1NP), 25-hydroxy vitamin D, tartrate resistant acid phosphatase-5b (TRACP-5b) and osteocalcin.ConclusionsSGLT2 inhibitors may negatively affect bone metabolism by increasing serum PTH, CTX, and decreasing serum ALP. This conclusion needs to be verified by more studies due to the limited number and quality of included studies.Systematic review registrationPROSPERO, identifier CRD42023410701

Changes in Testing and Treatment Methods in Osteoporosis Care.

Osteoporosis treatment plays a crucial role in preventing fractures, particularly in bedridden patients. We conducted a questionnaire survey presenting hypothetical clinical cases in 2015 and 2020 to investigate trends over a 5-year period. The target population included physicians working in clinics and hospitals within our neighbourhood. The cases were presented, and the questionnaire was administered in a confidential format. The orthopaedic surgeons were matched for age and practice, resulting in 74 cases being included in the analysis. Comparing the 2015 and 2020 results, we observed a notable increase in physicians who would perform "bone mineral density measurements of the lumbar spine and hip." Furthermore, there was a significant rise in the percentage of respondents willing to test for bone metabolic markers, such as serum type I collagen cross-linked N-telopeptide (NTX), procollagen I N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b (TRACP-5b). Regarding therapeutic agents, bisphosphonates decreased in usage, whereas parathyroid hormone and romosozumab witnessed an increase. In conclusion, the percentage of physicians requesting bone mineral density measurements of the lumbar spine and hip increased over the five-year period. In addition, more physicians chose to utilise bone metabolic markers due to their ease of measurement through blood tests and reduced diurnal variation. Finally, there was a marked trend towards the administration of drugs capable of rapidly and effectively increasing bone mineral density at an early stage of treatment.

Prognostic value of serum tartrate‑resistant acid phosphatase‑5b for bone metastasis in patients with resectable breast cancer.

Bone metastasis significantly affects the quality of life of patients with metastatic breast cancer, and can shorten overall survival. Identifying patients with early-stage breast cancer at high risk for bone metastasis and preventing bone metastasis may lead to a better quality of life and prolonged survival. The present study investigated whether serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone turnover marker, can be a prognostic factor for bone metastasis. Female patients who underwent resectable breast surgery between May 2002 and August 2006 were consecutively investigated. A total of 304 patients with a median follow-up of 3,722 days were retrospectively analyzed. TRACP-5b levels in sera prepared from patients' blood drawn preoperatively without any presurgical treatments were measured using an enzyme-linked immunosorbent assay. The cutoff of TRACP-5b levels, in order to separate patients into high and low TRACP-5b groups, was set at median (347 mU/dl). The associations of clinicopathological factors, including TRACP-5b, with bone metastasis-free interval (BMFI), which was defined as the duration between surgery and the diagnosis of bone metastasis at any time point, were examined. Multivariate analysis of various clinicopathological features revealed that lymph node metastasis and histological grade were independent factors associated with BMFI (P=0.017 and 0.030, respectively). In patients with node-positive breast cancer (n=114), a high TRACP-5b level and a high grade were significantly and independently associated with worse BMFI (log-rank P=0.041 and 0.011, respectively). In conclusion, these findings indicated that TRACP-5b may predict bone metastasis in patients with node-positive breast cancer.

Association of serum sodium levels with fractures and mortality in patients undergoing maintenance hemodialysis.

Hyponatremia is implicated in pathological bone resorption and has been identified as a risk factor for bone fracture in the general population. However, there are limited data on the association between serum sodium levels and fracture risk in patients undergoing hemodialysis (HD). We analyzed a historical cohort of 2220 maintenance HD patients to examine the association between serum sodium levels and the risk of fracture and mortality. We also examined the association between serum sodium levels and osteoporosis, based on metacarpal bone mineral density, in a subcohort of 455 patients with available data. In addition, we examined the association between serum sodium levels and bone turnover markers in a separate cross-sectional cohort of 654 maintenance HD patients. During a median follow-up of 5.4years, 712 patients died, 113 experienced clinical fractures, and 64 experienced asymptomatic vertebral fractures. Lower serum sodium levels were associated with an increased risk of mortality (HR 1.06 per 1mEq/L decrease; 95% CI 1.03-1.09) but not with the risk of clinical fracture (HR 1.04 per 1mEq/L decrease; 95% CI 0.97-1.11). A similar lack of association was observed for asymptomatic vertebral fracture and any fracture. Serum sodium levels were also not associated with osteoporosis in a subcohort with available data (n = 455) or with bone alkaline phosphatase or tartrate-resistant acid phosphatase-5b in a separate cross-sectional cohort. Serum sodium levels were associated with mortality but not with fracture risk, osteoporosis, or bone turnover markers in maintenance HD patients.

Morinda officinalis polysaccharide promotes the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells via microRNA-210-3p/scavenger receptor class A member 3.

Morinda officinalis polysaccharide (MOP) is the bioactive ingredient extracted from the root of Morinda officinalis, and Morinda officinalis is applied to treat osteoporosis (OP). The purpose of this study was to determine the role of MOP on human bone marrow mesenchymal stem cells (hBMSCs) and the underlying mechanism. HBMSCs were isolated from bone marrow samples of patients with OP and treated with MOP. Quantitative real-time polymerase chain reaction was adopted to quantify the expression of microRNA-210-3p (miR-210-3p) and scavenger receptor class A member 3 (SCARA3) mRNA. Cell Counting Kit-8 assay was employed to detect cell viability; Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling assay and flow cytometry were adopted to detect apoptosis; Alkaline Phosphatase (ALP) activity assay kit was applied to detect ALP activity; Western blot was executed to quantify the expression levels of SCARA3, osteogenic and adipogenic differentiation markers. Ovariectomized rats were treated with MOP. Bone mineral density (BMD), serum tartrate-resistant acid phosphatase 5b (TRACP 5b), and N-telopeptide of type I collagen (NTx) levels were assessed by BMD detector and Enzyme-linked immunosorbent assay kits. It was revealed that MOP could promote hBMSCs' viability and osteogenic differentiation and inhibit apoptosis and adipogenic differentiation. MOP could also upregulate SCARA3 expression through repressing miR-210-3p expression. Treatment with MOP increased the BMD and decreased the TRACP 5b and NTx levels in ovariectomized rats. MOP may boost the osteogenic differentiation and inhibit adipogenic differentiation of hBMSCs by miR-210-3p/SCARA3 axis.

Long-term effects of denosumab on bone mineral density and turnover markers in patients undergoing hemodialysis

IntroductionDenosumab, a fully human anti-RANKL monoclonal antibody, is a widely used osteoporosis treatment that is increasingly being used in patients undergoing dialysis; however, its long-term efficacy and safety in these patients remain unknown.Materials and methodsThis observational study comprised individuals aged ≥ 20 years undergoing hemodialysis and receiving denosumab. After denosumab administration, we analyzed the long-term changes in bone mineral density (BMD) and levels of bone turnover markers (BTMs) and calcium.ResultsThe study included 45 patients who have been receiving denosumab for a median duration of 3.8 (interquartile range, 2.5–6.7) years. Tartrate-resistant acid phosphatase 5b (TRACP-5b) levels decreased from a median of 595 (434–778) mU/dL at baseline to 200 (141–430) mU/dL after 6 months of denosumab administration (P < 0.001) and remained low thereafter. Similarly, bone-specific alkaline phosphatase (BAP) levels decreased from a median of 18.2 (15.9–25.8) μg/L at baseline to 12.4 (9.9–15.6) μg/L after 6 months (P < 0.001) and remained low thereafter. Meanwhile, BMD, as assessed with dual energy X-ray absorptiometry and measured at the distal 1/3 of the radius, did not decrease (0.465 ± 0.112 g/cm2 at baseline vs. 0.464 ± 0.112 g/cm2 after administration; P = 0.616). Regarding hypocalcemia, corrected calcium levels reached were the lowest at 7 days after administration and normalized within 30 days.ConclusionThe study showed long-term suppression of TRACP-5b and BAP levels and sustaining BMD after denosumab administration over an extended period in patients undergoing hemodialysis.

Targeting the Role of PRME in Regulating Bone Remodelling During Postmenopausal Osteoporosis.

Kariavattom Campus Postmenopausal osteoporosis (PMO) is an old age disorder associated with estrogen deficiency, which reduces bone mass and makes bones more prone to fracture. The present study was proposed to evaluate the invivo osteogenic efficiency of Pterospermum rubiginosum methanolic bark extract (PRME) in the PMO model. Molecular docking studies on transcription factor NFATC1 showed excellent interactions with phytochemical ligands with the lowest binding energies. Female Sprague Dawley (SD) rats (n=24) were divided into four groups, (n=6 each) sham control (Group I) and osteoporotic control (Group II) groups treated with saline, PRME (50 mg/kg/day) and alendronate (10 mg/kg/day) treated with Group III and Group IV (n=6) respectively. The serum tartrate-resistant acid phosphatase 5b and cathepsin-K also exhibited a significant rise after PRME treatment 12.33±2.30 mU/ml and 427.68±46.97 pg/ml, respectively. DEXA results exhibited a remarkable increase in total bone mineral content and density values in PRME-treated animals (0.175±0.002 g/cm2) and (7.95±0.23 g) when compared to osteoporotic control (0.163±0.004 g/cm2) and (6.83±0.34 g). Long-term toxicity study revealed that PRME is non-toxic, up to 100 mg/kg bodyweight for 6 months. Our findings suggest PRME protects osteoporotic SD rats from PMO damage resulting from estrogen deficiency by regulating bone remodelling markers and upregulating BMD indices.

Bone metabolism and inflammatory biomarkers in radiographic and non-radiographic axial spondyloarthritis patients: a comprehensive evaluation.

Axial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study aimed to evaluate the relationship between the markers of inflammation and bone turnover in r-axSpA patients and nr-axSpA patients. A cross-sectional study included 29 r-axSpA patients, 10 nr-axSpA patients, and 20 controls matched for age and sex. Plasma markers related to bone remodeling such as human procollagen type 1 N-terminal propeptide (P1NP), sclerostin, tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were measured by an ELISA kit. A panel of 92 inflammatory molecules was analyzed by proximity extension assay. R-axSpA patients had decreased plasma levels of P1NP, a marker of bone formation, compared to controls. In addition, r-axSpA patients exhibited decreased plasma levels of sclerostin, an anti-anabolic bone hormone, which would not explain the co-existence of decreased plasma P1NP concentration; however, sclerostin levels could also be influenced by inflammatory processes. Plasma markers of osteoclast activity were similar in all groups. Regarding inflammation-related molecules, nr-axSpA patients showed increased levels of serum interleukin 13 (IL13) as compared with both r-axSpA patients and controls, which may participate in the prevention of inflammation. On the other hand, r-axSpA patients had higher levels of pro-inflammatory molecules compared to controls (i.e., IL6, Oncostatin M, and TNF receptor superfamily member 9). Correlation analysis showed that sclerostin was inversely associated with IL6 and Oncostatin M among others. Altogether, different inflammatory profiles may play a role in the development of the skeletal features in axSpA patients particularly related to decreased bone formation. The relationship between sclerostin and inflammation and the protective actions of IL13 could be of relevance in the axSpA pathology, which is a topic for further investigation.