Bone Markers Research Articles

Micro-Nanostructured Polymeric Scaffolds for Bone Tissue Engineering

While bone tissue allograft and autograft are commonly used in bone healing, their application is limited by factors such as availability, donor site morbidity, and immune response to the grafted tissue. Tissue-engineered implants, such as acellular or cellular polymeric structures, offer a promising alternative, and are a current trend in tissue engineering. Leveraging recent advancements in bone tissue engineering (BTE), we utilize 3D printing to develop biodegradable scaffolds that combine mechanical strength and bioactivity to facilitate bone repair and regeneration. This study focuses on the design and fabrication of mechanically competent 3D printed poly (L-lactic acid) (PLLA) micro-structured scaffolds. These scaffolds are enhanced with collagen type I nanofibrils to create bioactive scaffolds that promote tissue regeneration. The performance of these mechanically competent, micro-nanostructured polymeric matrices, in combination with bone marrow stromal cells (BMSCs), is evaluated in PLLA and PLLA-collagen scaffolds. The resulting micro-nanostructured PLLA-Collagen scaffolds mimic trabecular bone architecture, mechanical strength, and the extracellular matrix environment found in native bone tissue. The composite PLLA-collagen scaffolds exhibit mechanical properties in the mid-range of human trabecular bone. Both PLLA and PLLA-Collagen scaffolds support human BMSCs adhesion, proliferation, and osteogenic differentiation. A significantly higher number of implanted host cells are distributed in the PLLA-Collagen scaffolds with greater bone density, more uniform cell distribution, and attachment compared to the PLLA microstructure. Additionally, the biomimetic collagen nanostructure potently induces osteogenic transcription evidenced by increased alkaline phosphatase activity and upregulation of bone markers such as sialoprotein and collagen type I, ultimately guiding stem cell-mediated formation of a mature, mineralized bone matrix throughout the interconnected scaffold pores. This study underscores the benefits of micro-nanostructured scaffolds in successfully generating the inductive microenvironment of native bone extracellular matrix, triggering the cascade of cellular events required for functional bone regeneration, repairing critical-sized bone defects, and ultimately serving as an alternative material platform for bone regeneration, thereby instilling confidence in the potential of our research.

Cystinosis-associated metabolic bone disease across ages and CKD stages 1-5D/T.

The pathophysiology of cystinosis-associated metabolic bone disease is complex. We hypothesized a disturbed interaction between osteoblasts and osteoclasts. Binational cross-sectional multicenter study. Hospital clinics. One hundred and three patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1-5D/T. Ten key bone markers. Skeletal complications occurred in two-thirds of the patients, with adults having a five-fold increased risk compared to children. Patients with CKD stages 1-3 showed reduced z-scores for serum phosphate and calcium, suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation. Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counterregulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia may promote progressive bone loss.

The potent osteo-inductive capacity of bioinspired brown seaweed-derived carbohydrate nanofibrous three-dimensional scaffolds.

This study aimed to investigate the osteo-inductive capacity of a fucoidan polysaccharide network derived from brown algae on human adipose-derived stem cells (HA-MSCs) for bone regeneration. The physiochemical properties of the scaffold including surface morphology, surface chemistry, hydrophilicity, mechanical stiffness, and porosity were thoroughly characterized. Both in vitro and in vivo measurements implied a superior cell viability, proliferation, adhesion, and osteo-inductive performance of obtained scaffolds compared to using specific osteogenic induction medium with increased irregular growth of calcium crystallites, which mimic the structure of natural bones. That scaffold was highly biocompatible and suitable for cell cultures. Various examinations, such as quantification of mineralization, alkaline phosphatase, gene expression, and immunocytochemical staining of pre-osteocyte and bone markers confirmed that HAD-MSCs differentiate into osteoblasts, even without an osteogenic induction medium. This study provides evidence for the positive relationship and synergistic effects between the physical properties of the decellularized seaweed scaffold and the chemical composition of fucoidan in promoting the osteogenic differentiation of HA-MSCs. Altogether, the natural matrices derived from brown seaweed offers a sustainable, cost-effective, non-toxic bioinspired scaffold and holds promise for future clinical applications in orthopedics.

High-intensity interval training improves bone remodeling, lipid profile, and physical function in multiple sclerosis patients

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease due to an autoimmune chronic inflammatory response, yet the etiology is currently not completely understood. It is already known that physical activity plays an essential role in improving quality of life, especially in neuropathological conditions. The study was aimed to investigate the possible benefits of high-intensity interval training (HIIT) in bone and lipid metabolism markers, and neuromotor abilities in MS patients. 130 participants were recruited; 16 subjects with MS met the inclusion criteria and were included in the data analysis. The patients were randomly assigned to two groups: a Control group (CG) (34.88 ± 4.45 yrs) that didn’t perform any physical activity and the Exercise group (EG) (36.20 ± 7.80 yrs) that performed HIIT protocol. The training program was conducted remotely by a kinesiologist. It was performed three times a week for 8 weeks. At the beginning (T0) and the end of the study (T1) physical function tests, bone remodelling markers, and lipid markers analyses were performed. After 8 weeks of training the wall squat (s) (T0 = 27.18 ± 4.21; T1 = 41.68 ± 5.38, p ≤ 0.01) and Time Up and Go test (s) (T0 = 7.65 ± 0.43; T1 = 6.34 ± 0.38 p ≤ 0.01) performances improved; lipid markers analysis showed a decrease in Total (mg/dl) (T0 = 187.22 ± 15.73; T1 = 173.44 ± 13.03, p ≤ 0.05) and LDL (mg/dl) (T0 = 108 ± 21.08; T1 = 95.02 ± 17.99, p < 0.05) cholesterol levels. Additionally, the levels of osteocalcin (µg/L), a marker of bone formation increased (T0 = 20.88 ± 4.22; T1 = 23.66 ± 6.24, p < 0.05), 25-OH Vitamin D (µg/L) improved after 8 weeks (T0 = 21.11 ± 7.11; T1 = 27.66 ± 7.59, p < 0.05). HIIT had an effect on lower limb strength and gait control, improved bone formation, and lipid management, in MS 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.

Role of Adenosine Receptor Agonist in a Rat Model of Diabetic-Induced Osteoporosis

Abstract Background Diabetic osteoporosis is caused by chronic hyperglycemia, oxidative stress, advanced glycation end products accumulation and microvascular changes. All these alter signaling pathways involved in bone metabolism. Adenosine receptors (ARs) are expressed in the bone and might play a role in bone homeostasis. Recent data reveal that A2AAR plays a key role in bone homeostasis and regeneration. However, whether it has a role in treatment of osteoporosis induced by diabetes has not been reported. Objective The aim of the present study was to evaluate the effect of CGS-21680, an A2A adenosine receptor agonist, in ameliorating osteoporosis induced by diabetes in a rat model. Materials and Methods Forty adult male Albino-rats were allocated into four groups: Group I: control group; Group II: untreated diabetic induced osteoporosis group; Group III: insulin treated diabetic-induced osteoporosis group; Group IV: adenosine receptor agonist treated diabetic-induced osteoporosis group. Diabetes was induced by a single intraperitoneal injection of STZ at a dose of 40 mg/Kg body weight. At the end of the study the bone marker osteocalcin, serum glucose, insulin, tumor necrosis factor-α, malondialdehyde, glutathione peroxidase, calcium and phosphorus were measured, and bone histopathological analysis was done. Results Compared with the untreated diabetic groups, the A2A adenosine receptor agonist treated group showed less bone loss, which was revealed by the increased cortical bone thickness and trabecular thickness. In addition to decreased oxidative damage and inflammation. Conclusion The decreased oxidative stress and inflammation in the A2A adenosine receptor agonist treated group supports a beneficial effect of A2AAR stimulation in treatment of diabetic induced osteoporosis, which was demonstrated by the improvement in bone microarchitecture.

Evaluation of Bone Markers in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) has affected over 387 million patients globally, expected to reach 592 million by the end of 2035. It is a metabolic disorder characterized by chronic hyperglycemia caused by either insulin deficiency, insulin resistance, or both. The present study was designed to estimate the levels of different bone markers; serum Vitamin D, alkaline phosphatase, phosphorus, and calcium in patients with type 2 DM (T2DM). The study was conducted on patients aged 20-50 years diagnosed with T2DM, who were attending the outpatient/inpatient department of internal medicine. The levels of calcium were decreased in the patients with diabetes and also the study proved a negative correlation between calcium and random plasma glucose (RPG). There was a significant negative correlation between RPG and serum 25(OH)D3. We conclude that Vitamin D insufficiency is frequent in Moradabad, Uttar Pradesh. Sunshine exposure daily for 15 min on the face and hands is necessary to elevate the sunlight Vitamin D levels.

Effect of Caponization on Blood Parameters and Tibia Characteristics in Crossbred Chickens Derived from Conserved Breed Hens and Meat Roosters

Abstract The effect of caponization on the level of testosterone, biochemical bone markers as well as on the geometrical, densitometric, structural, mechanical and microstructural characteristics of the tibia of capons was the subject of this study. The study was conducted on 80 hybrids obtained from the crossing of Rhode Island Red (R-11) hens and meat roosters (Ross 308). Cockerels were surgically castrated at 8 week of age and then fattened until the 24th week of life. The results indicated that the serum testosterone (P&lt;0.01), osteocalcin (P&lt;0.05), and osteoprotegerin (OPG) (P&lt;0.05) concentration were significantly lower, while the serum receptor activator of nuclear factor kappa-B ligand (RANKL) (P&lt;0.01), RANKL/OPG ratio (P&lt;0.05) and alkaline phosphatase concentrations (P&lt;0.05) were significantly higher in capons. The tibia weight, the relative tibia weight, and the cross-sectional area of tibia were significantly higher (P&lt;0.05) in cockerels, while capons had higher (P&lt;0.05) body weight and transversal external diameter of tibia. Moreover, the bone ash, calcium and phosphorus content, bone mineral density and bone mineral content, and also yield load, ultimate load, work to fracture, as well as Young’s modulus, bending moment, yield stress and ultimate stress were significantly lower (P&lt;0.05) in capons. Caponization also caused a significant reduction in the percentage volume of bone (P&lt;0.05) in the proximal epiphyses of the tibia, as well as changes in its microarchitecture (P&lt;0.05) (fewer trabeculae and connections between trabeculae, thicker trabeculae and larger spaces between trabeculae). Concluding, caponization disrupts the homeostasis and microstructure of the tibia, and this results in a decrease in the mechanical strength of the tibia, making it more susceptible to deformation.

Comparative Analysis of Myokines and Bone Metabolism Markers in Prepubertal Vegetarian and Omnivorous Children.

The role of bone and muscle as endocrine organs may be important contributing factors for children's growth and development. Myokines, secreted by muscle cells, play a role in regulating bone metabolism, either directly or indirectly. Conversely, markers of bone metabolism, reflecting the balance between bone formation and bone resorption, can also influence myokine secretion. This study investigated a panel of serum myokines and their relationships with bone metabolism markers in children following vegetarian and omnivorous diets. A cohort of sixty-eight healthy prepubertal children, comprising 44 vegetarians and 24 omnivores, participated in this study. Anthropometric measurements, dietary assessments, and biochemical analyses were conducted. To evaluate the serum concentrations of bone markers and myokines, an enzyme-linked immunosorbent assay (ELISA) was used. The studied children did not differ regarding their serum myokine levels, except for a higher concentration of decorin in the vegetarian group (p = 0.020). The vegetarians demonstrated distinct pattern of bone metabolism markers compared to the omnivores, with lower levels of N-terminal propeptide of type I procollagen (P1NP) (p = 0.001) and elevated levels of C-terminal telopeptide of type I collagen (CTX-I) (p = 0.018). Consequently, the P1NP/CTX-I ratio was significantly decreased in the vegetarians. The children following a vegetarian diet showed impaired bone metabolism with reduced bone formation and increased bone resorption. Higher levels of decorin, a myokine involved in collagen fibrillogenesis and essential for tissue structure and function, may suggest a potential compensatory mechanism contributing to maintaining bone homeostasis in vegetarians. The observed significant positive correlations between myostatin and bone metabolism markers, including P1NP and soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), suggest an interplay between muscle and bone metabolism, potentially through the RANK/RANKL/OPG signaling pathway.

Efficacy of Oral Magnesium on Bone Regeneration and Implant Stability in Immediate Dental Implants: A Randomized Controlled Trial.

The successful osseointegration around immediate implants requires high quality and quantity of osteogenesis around them. The role of magnesium as a boneenhancing mineral, and as an adjunctive analgesic has been well documented in orthopedic literature. However, there is a paucity of literature in its role in successful osseointegration around immediate implants. This randomized controlled trial sought to assess the promising impact of magnesium on osseointegration by examining various aspects of implant stability, correlating them with serum bone markers, and establishing a foundation for future research on its potential as a potent analgesic. Immediate implant placement was done after the extraction of the indicated mandibular molar tooth, and all the patients were segregated into 2 groups (Placebo- Lactose, and Magnesium citrate). Bone regenerate in the peri-implant area was assessed radiographically immediate post-operatively, on the 6th week and 12 weeks. Implant stability was measured immediate post-operatively, at the 4th week and 12th week. Serum parameters were procured pre-operatively and post-operatively for serum calcium, serum alkaline phosphatase (ALP), and serum parathyroid hormone at the 8th week, and serum vitamin D3 levels preoperatively. 54 immediate implants placed showed the demographics and baseline serum, clinical, and radiographic parameters were comparable in both groups. Analysis of Implant Stability Quotient at 12th week showed statistically significant difference in intervention group both on intergroup and intragroup analysis. Radiodensity measurement showed a statistically significant difference in both intragroup and intergroup analysis in the intervention group at the 6th and 12th week. In bone gap analysis, the difference in mean change in the horizontal bone gap (HG) at 6 weeks was non-significant while the difference in HG at the 12th week was significant in the intervention group. On intragroup analysis, mean change HG at 6 weeks and 12 weeks both were significant only in intervention group. Intergroup analysis of vertical bone gap (VG) 12 and VG 12-0 (mean difference in the vertical bone gap from 12th week-day 0) showed a statistically significant difference in the intervention group. On intragroup analysis, VG 12 was significantly better in the intervention group. On serum analysis, ALP post-operatively was found to be significantly raised (P=0.013) in intervention group. Numerical rating Scale (NRS) analysis showed a significant decrease in post-op day 5 and 7, (P=0.017) and (P=0.002) respectively. The oral magnesium citrate supplementation after immediate implant placement helps in enhancing the stability of the immediate implants, along with improved radiodensity around them which was found to be statistically significant. It also helps in reducing the horizontal, and vertical gap around the implant and has significant analgesic potential.

Bone health in young adults with type 1 diabetes and progressive eGFR decline

BackgroundType 1 Diabetes (T1D) is associated with increased risk of fractures, worsened by presence of microvascular complications. This study’s objective is to determine the impact of progressive decline in estimated glomerular filtration rate (eGFR) on bone biomarkers and bone microarchitecture in youth with T1D.MethodsSlopes of eGFR were calculated using measures obtained at four timepoints from adolescence to young adulthood. Participants were identified as eGFR decliners if eGFR decreased ≥ 3ml/min/1.73m2/year. Bone health was assessed in young adulthood by high resolution peripheral quantitative computed tomography (HRpQCT Xtreme CTII) and bone biomarkers; osteocalcin, procollagen 1 intact n-terminal pro-peptide (P1NP), c-terminal telopeptide (CTX), and bone specific alkaline phosphatase. The relationship between diabetes duration, glycated hemoglobin, body mass index (BMI) and vitamin D level on bone biomarkers and microarchitecture was evaluated. Linear regression analysis was used for the statistical analysis in this study.ResultsNinety-nine study participants were studied with longitudinal evaluation of eGFR over 7.4 ± 1.0 years with mean age of 14.7 ± 1.7 years at baseline. Cross sectional evaluation of bone was performed at 21.3 ± 2.1 years. 44% participants had eGFR decline and showed 5% higher cortical porosity diameter than non-decliners (p = 0.035). Greater diabetes duration was associated with higher trabecular separation (p = 0.004) and lower trabecular number (p = 0.01). Higher level of 25 hydroxy-vitamin D was associated with lower trabecular separation (p = 0.01). Elevated glycated hemoglobin (p = 0.0008) and BMI (p = 0.009), were associated with lower markers of bone formation.ConclusionMild increase in cortical porosity diameter was found in youth with T1D and eGFR decline, however, overall measures of bone microarchitecture on HR-pQCT were similar between both groups and there were no statistically significant changes in bone biomarkers. Hence, skeletal impairments were limited in youth with different eGFR trajectories near peak bone mass. Longitudinal HR-pQCT studies are needed to further understand the impact of eGFR decline on bone microarchitecture. Optimal glycemic control, normal BMI and vitamin D status were supported by this study as important markers for good bone health.

#442 Hyperparathyroidism, serum phosphorus and dietary intake in hemodialysis patients: is there a novel relationship?

Abstract Background and Aims Hyperparathyroidism (HPTH), classified when intact parathyroid hormone (iPTH) serum levels are above 585 pg/mL, is a common complication in patients undergoing maintenance hemodialysis (HD). Despite there is little evidence about the relationship between iPTH levels and nutritional status, the intervention frequently focusses on appropriate management of mineral and bone markers, being the decrease of serum and dietary phosphorus some of the targets. The aim of this study was to investigate the association between iPTH, serum phosphorus levels and dietary intake. Method This was a cross-sectional, multicenter, observational study with 561 patients on HD treatment from 37 dialysis centers across Portugal. Clinical parameters, body composition and dietary intake (obtained from a Food Frequency Questionnaire) were assessed. For the analysis, patients were divided in 3 groups depending on their iPTH levels: a) iPTH&amp;lt;130, b) iPTH between 130-585 and c) iPTH &amp;gt;585 pg/mL. The association between PTH, serum phosphorus and dietary intake was analyzed with linear regression models. A p-value lower than 0.05 was considered statistically significant. Results Patients’ mean age was 68 ± 14 years, median HD vintage was 65 (IQR: 43-106) months and 58.8% were men. From the whole sample, 13.9% presented a iPTH &amp;lt;130 pg/mL, 59.3% between 130-585 pg/mL and 23.2% &amp;gt;585 pg/mL. Patients with higher iPTH levels were those with longer HD vintage (p = 0.021) and lower age (p = 0.002). At the same time, showed higher serum phosphorus (p = 0.005), serum calcium (p = 0.027), Ca/P product (p &amp;lt; 0.001), albumin (p = 0.016) and caffeine intake (p = 0.009). In addition, a lower dietary intake of phosphorus (p = 0.044), fiber (p = 0.047), riboflavin (p = 0.031) and folate (p = 0.011) were observed in patients with higher iPTH levels. In the linear regression models, higher serum phosphorus predicted higher iPTH levels, even in the adjusted model (p = 0.019). However, a lower phosphorus intake was a predictor of higher iPTH levels, also in the model adjusted to age, gender, serum phosphorus, dialysis adequacy (Kt/V) and dialysis vintage (p = 0.035). The same result was observed when considering the dietary fiber intake in the model (p = 0.048). No significant differences in body composition parameters were found. Conclusion Our results bring new data on the relationship between dietary intake and iPTH values. Despite higher serum phosphorus was observed in patients with HPTH, an opposite association was noted regarding dietary phosphate and fiber as lower intakes predicted higher iPTH values. Moreover, a poorer dietary intake, considering riboflavin and folate was observed in the HPTH group.

Long-Term Differential Effects of Gastric Bypass and Sleeve Gastrectomy on Bone Mineral Density

Abstract Context The association of obesity with bone fragility fractures is complex and non-linear. Despite good efficacy on weight loss, bariatric surgery (BS) is also associated with bone loss. However, we lack information on risk factors of the long-term deleterious effects of BS on the skeleton. Objective We aimed to assess the factors associated with low bone mineral density (BMD) performed a long time after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Methods This cross-sectional study involved patients at a long distance from their BS that underwent dual-energy x-ray absorptiometry (DXA) with biological factors (vitamins, micronutrients, bone and inflammation biomarkers). Simple and multiple linear models (stepwise and parsimony approach) were developed. Results A total of 131 patients (91 RYGB, 40 SG) underwent DXA (51.8 ± 11.08 years, 87.8% women). At a mean of 6.8 ± 3.7 years after surgery, the mean weight loss was –28.6 ± 9.6%, and only 6 patients (5.7%) had a T-score less than or equal to ­2.5. On univariate analysis, BMD was lower in the RYGB than in the SG group (P &amp;lt; .001) at all sites, despite similar fat and fat-free mass and weight loss. Serum parathyroid hormone and phosphate levels were higher in RYGB than SG patients. A total of 10.1% of patients showed vascular calcifications. On multivariable analysis, BMD remained different between surgery groups after adjustment for age, body mass index, ethnicity, and sex. The model-adjusted R2 values were 0.451 for the total hip; 0.462 the femoral neck, and 0.191 the lumbar spine for the inflammation model; 0.458, 0.462, and 0.254, respectively, for the bone marker model; and 0.372, 0.396, and 0.142 for the vitamin model. Serum zinc, ferritin, and uric acid levels were the markers associated with BMD to a low extent. Conclusion BMD differed depending on the BS procedure. A few biological markers may be associated weakly with BMD well after the surgery.

Efficacy of sintered Zinc-doped fluorapatite scaffold as an antimicrobial regenerative bone filler for dental applications

ObjectivesThe objective of this study was to assess whether zinc-doped fluorapatite (ZnFA) could serve as an effective antimicrobial dental bone filler for bone regeneration compared to autografts. MethodsFA and 2 % zinc-doped FA (2ZnFA) were synthesized and characterized in-house. Compressed and sintered FA and 2ZnFA disks were incubated with bacteria to assess antimicrobial properties. Adipose-derived stem cells were cultured on these discs to evaluate the surfaces’ ability to support cell growth and promote osteogenic differentiation. Surfaces exhibiting the highest expressions of the bone markers osteopontin and osteocalcin were selected for an in vivo study in a rat mandibular defect model. Twenty rats were divided into 5 groups, equally, and a 5 mm surgical defect of the jaw was left untreated or filled with 2ZnFA, FA, autograft, or demineralized bone matrix (DBM). At 12 weeks, the defects and surrounding tissues were harvested and subjected to microCT and histological evaluations. ResultsStandard techniques such as FTIR, ICP-MS, fluoride probe, and XRD revealed the sintered FA and ZnFA's chemical compositions and structures. Bacterial studies revealed no significant differences in surface bacterial adhesion properties between FA and 2ZnFA, but significantly fewer bacterial loads than control titanium discs (p < 0.05). Cell culture data confirmed that both surfaces could support cell growth and promote the osteogenic differentiation of stem cells. MicroCT analysis confirmed statistical similarities in bone regeneration within FA, 2ZnFA, and autograft groups. ConclusionThe data suggests that both FA and 2ZnFA could serve as alternatives to autograft materials, which are the current gold standard. Moreover, these bone fillers outperformed DBM, an allograft material commonly used as a dental bone void filler. Clinical SignificanceThe use of FA or 2ZnFA for treating mandibular defects led to bone regeneration statistically similar to autograft repair and significantly outperformed the widely used dental bone filler, DBM. Additional translational research may confirm FA-based materials as superior substitutes for existing synthetic bone fillers, ultimately enhancing patient outcomes.

Self Emulsifying Delivery System of Cissus quadrangularis: Evidence of Enhanced Efficacy and Promising Pharmacokinetic Profile in the Management of Osteoporosis.

Treatment therapies used to manage osteoporosis are associated with severe side effects. So worldwide herbs are widely studied to develop alternative safe & effective treatments. Cissus quadrangularis (CQ) has a significant role in bone health and fracture healing. It is documented that its extracts increase osteoblastic differentiation & mineralization. Currently, Cissus quadrangularis is available in the form of tablets in the market for oral delivery. But these conventional forms are associated with poor bioavailability. There is a need for a novel drug delivery system with improving oral bioavailability. Therefore, a Cissus quadrangularis-loaded self-emulsifying drug delivery system (CQ-SEDDS) was developed which disperses rapidly in the gastrointestinal fluids, yielding nano-emulsions containing a solubilized drug. This solubilized form of the drug can be easily absorbed through lymphatic pathways and bypass the hepatic first-pass effect. The emulsification efficiency, zeta potential, globule size, in-vitro dissolution, ex-vivo, in-vivo and bone marker studies were performed to assess the absorption and permeation potential of CQ incorporated in SEDDS. CQ-SEDDS with excipients Tween 80, Cremophor RH40, Transcutol HP & α-Tocopherol acetate had shown about 76% enhancement in the bioavailability of active constituents of CQ. This study provided the pre-clinical data of CQ-SEDDS using osteoporotic rat model studies.

Abstract PO1-12-02: Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients

Abstract Denosumab (Dmab), an inhibitor of osteoclast activity and proliferation is approved for treatment of women on aromatase inhibitor (AI) therapy for early breast cancer (60 mg Q 6-months) and metastatic disease (120 mg Q 4-weeks) to protect against bone loss and prevention of skeletal-related events (SREs). 60 mg given twice a year has shown fracture reduction, especially in women on aromatase inhibitor therapy, and recent data supports benefits in disease free survival, bone-metastasis free-survival and overall survival with Dmab in early breast cancer. It appears superior in reduction of SREs versus zoledronic acid (ZA) in established skeletal metastatic disease; thus, a preferred choice in the oncology setting. In the osteoporosis setting, withdrawal of Dmab therapy leads to a “rebound” increase of bone resorption, rapid bone loss and potential vertebral fractures. Increased risk of spontaneous and multiple vertebral fractures has been seen in this patient population. To prevent this, after discontinuation of Dmab, the addition of another anti-resorptive such as ZA is initiated. Dmab withdrawal events are uncommonly reported in patients with metastatic skeletal disease due to generally poor prognosis. Dmab given as 120 mg/month in this setting may need to be curtailed for a variety of indications including hypocalcemia, major dental procedures, osteonecrosis of the jaw or atypical femoral fracture. In the oncologic setting, it is unclear if discontinuation of Dmab will lead to rebound bone resorption or increased incidence of fractures. We describe the case is of a 32-year-old woman with a history of T2N3M1, oligometastatic breast cancer (solitary bone metastases at L1, biopsy-proven) that was ER/PR/HER2 positive. She was treated with neoadjuvant trastuzumab, pertuzumab, taxotere and carboplatin followed by bilateral mastectomy, and radiation to chest wall and L1. She received total estrogen blockade initially with GnRH-agonist and exemestane and ultimately bilateral salpingo-oophorectomy plus exemestane. She continues pertuzumab and trastuzumab (80 treatments to date) for the past 5 years and denosumab 120 mg/month for 14 treatments and then every 3 months, 20 total treatments. Development of hip pain (regular runner) and concern for atypical fracture vs metastatic disease led to bone scan and PET/CT. Metastatic disease was ruled out and stress reaction was diagnosed. Dmab therapy was discontinued with monitoring of her metabolic bone turnover. 1 year after her last Dmab injection, bone turnover markers began to increase and ultimately demonstrated a very significant “rebound phenomenon.” Subsequently, a single dose of 120 mg denosumab decreased bone markers to previously low levels which remain low on routine monitoring, table below. In future, ZA will be initiated and continued on a yearly basis. Dmab has replaced ZA in managing bone health in breast cancer patients. Many oncologists use this without the assistance of bone health endocrinologists, who are an integral part of our cancer center. Bone modifying agents are often discontinued without consideration of the negative impact this may have. As this is a major survivorship issue, we document this case with literature review, to raise awareness for oncologists prescribing these medications. Citation Format: Susan Tannenbaum, Alvaro Alvarez Soto, Pamela Taxel. Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients [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 PO1-12-02.

Effect of oxytocin receptor antagonist (GSK-221-149-A) on mandibular bone porosity in peri-menopausal rats

The period of peri-menopause (PMP) is characterized by hormonal fluctuations that impact the strength and health of bones. Oxytocin (OX), a small peptide known to be present in bone tissue, is the focus of this study. The objective of this research is to gain a better understanding of how OX precisely functions in the remodeling process of the mandibular bone. This understanding is seen as a crucial step in preventing the loss of both cortical and trabecular bone during the PMP. The current findings indicate that OX plays a role in preserving both compact and trabecular bone tissues, enhancing the mineral-to-matrix ratio, and regulating bone markers. Furthermore, it reduces porosity in both cortical and trabecular bone levels. Interestingly, these effects are reversed when an oxytocin receptor antagonist (GSK-221,149-A) is introduced, suggesting that OX’s bone-preserving action is primarily mediated through the oxytocin receptor, rather than other mechanisms.

Circulating plasma-derived extracellular vesicles expressing bone and kidney markers are associated with neurocognitive impairment in people living with HIV.

Although effective antiretroviral therapy (ART) has improved the life expectancy of people with HIV (PWH), the prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) persist, and it is associated with systemic and neuro-inflammatory processes that could impact other organ systems. However, the complex signaling mechanisms between the bone-kidney systems and the brain in HAND remain unknown. Extracellular vesicles (EVs) play a potential role in inter-organ communication and are involved in regulating cell activity in distant tissues. In this study, we examined whether levels of EVs from bone-and kidney-related cells associate with cognitive dysfunction and explored the relationship between kidney-bone EV axis in PWH experiencing cognitive deficits. EV subtypes were characterized in plasma from 61 PWH with either cognitive impairment (CI, n = 53) or normal cognition (NC, n = 8) based on the American Academy of Neurology criteria for HIV-associated dementia (HAD, n = 11), minor cognitive motor disorder (MCMD, n = 25) or asymptomatic neurocognitive impairment (ANI, n = 17) by spectral flow cytometry. EVs were profiled with markers reflecting bone and kidney cell origin. A support vector machine learning-based model was employed for analyses of EV phenotypes to predict the cognitive dysfunction. Plasma-EVs expressing osteocalcin, sclerostin, and nephrin were significantly higher in the cognitive impairment group compared to the normal cognition group. EVs bearing kidney cell markers correlated significantly with bone-derived EVs. A machine learning-based model, comprised of osteocalcin+, nephrin+, and CD24+ EVs predicted cognitive impairment in PWH on ART. Our study reveals that neurocognitive impairment in PWH is associated with increased levels of plasma EVs enriched with the bone markers osteocalcin and sclerostin and the kidney marker nephrin, suggesting that these EV subtypes may be novel candidate biomarkers for disease-spanning neurocognitive dysfunction. Moreover, the relationship between bone-derived EVs with kidney-derived EVs may suggest their role in mediating inter-organ crosstalk in the pathogenesis of HIV-associated cognitive impairment.

Chordoma cells possess bone-dissolving activity at the bone invasion front.

Chordomas are malignant tumors that destroy bones, compress surrounding nerve tissues and exhibit phenotypes that recapitulate notochordal differentiation in the axial skeleton. Chordomas recur frequently, as they resist radio-chemotherapy and are difficult to completely resect, leading to repeated bone destruction and local expansion via unknown mechanisms. Here, using chordoma specimens and JHC7 chordoma cells, we asked whether chordoma cells possess bone-dissolving activity. CT imaging and histological analysis were performed to evaluate the structure and mineral density of chordoma-invaded bone and osteolytic marker expression. JHC7 cells were subjected to immunocytochemistry, imaging of cell fusion, calcium dynamics and acidic vacuoles, and bone lysis assays. In patients, we found that the skull base invaded by chordoma was highly porous, showed low mineral density and contained brachyury-positive chordoma cells and conventional osteoclasts both expressing the osteolytic markers tartrate-resistant acid phosphatase (TRAP) and collagenases. JHC7 cells expressed TRAP and cathepsin K, became multinucleated via cell-cell fusion, showed spontaneous calcium oscillation, and were partly responsive to the osteoclastogenic cytokine RANKL. JHC7 cells exhibited large acidic vacuoles, and nonregulatory bone degradation without forming actin rings. Finally, bone-derived factors, calcium ions, TGF-β1, and IGF-1 enhanced JHC7 cell proliferation. In chordoma, we propose that in addition to conventional bone resorption by osteoclasts, chordoma cells possess bone-dissolving activity at the tumor-bone boundary. Furthermore, bone destruction and tumor expansion may occur in a positive feedback loop.

Dynamic influence of maternal education on height among Chinese children aged 0–18 years

BackgroundMaternal education is one of key factors affecting nurturing environment which significantly impacts children's height levels throughout their developmental stages. However, the influence of maternal education on children’s height is less studied. This study aims to investigate the dynamic influence of maternal education on children's height among Chinese children aged 0-18 years. MethodsChildren undergoing health examinations from January 2021 to September 2023 were included in this study. Clinical information including height, weight, maternal pregnancy history, blood specimens for bone metabolism-related indicators and maternal education level was collected. Children's height was categorized into 14 groups based on age and gender percentiles, following WHO 2006 growth standards. One-way analysis of variance (ANOVA), linear regression, chi-square test and Fisher's exact test were applied for data analysis. ResultsA total of 6269 samples were collected, including 3654 males and 2615 females, with an average age of 8.38 (3.97) for males and 7.89 (3.55) for females. Significant correlations between maternal education level, birth weight, birth order, weight percentile, vitamin D, serum phosphorus, alkaline phosphatase levels, and children's height were identified. Birth weight's influence on height varied across age groups. Compared with normal birth weight children, low birth weight children exhibited catch-up growth within the first 6 years and a subsequent gradual widening of the height gap from 6 to 18 years old. Remarkably, the impact of maternal education on height became more pronounced among children above 3–6 years old, which can mitigate the effect of low birth weight on height. ConclusionWe found that weight percentile, birth weight, birth order, bone marker levels, and maternal education level have significant effect on height. Maternal education attenuates the impact of low birth weight on height. The findings indicated that maternal education plays a consistent and critical role in promoting robust and healthy growth.