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Background: Acute-phase reactions (APRs) are common among people treated for the first time with zoledronate (ZOL). The current view is that both the APRs caused by ZOL and its efficacy are related to the mevalonic acid pathway. However, the relationship between APRs and ZOL efficacy remains unclear. Methods: This was a prospective observational cohort study involving postmenopausal women with osteoporosis in Shanghai, China, for 1 year. A total of 108 patients with an average age of 67.4 ± 5.8 years were treated with 5 mg intravenous ZOL for the first time. Data on demographic characteristics, APRs, blood counts, bone turnover markers, including C-telopeptide collagen crosslinks (CTX) and N-terminal propeptide of type 1 collagen (PINP), and bone mineral density (BMD) were collected. Results: (1) The results did not reveal a relationship between APRs and changes in bone turnover markers and BMD but showed that changes in body temperature (T) within 3 days after administration were positively correlated with changes in the BMD of the LS at Month 12 (β = 0.279 P = 0.034). (2) This effect was mediated mainly by changes in serum CTX (b = 0.046, 95% CI [0.0010–0.0091]). (3) The ROC curve revealed that when T increased by 1.95 °C, the sensitivity and specificity of identifying clinically important changes in LS BMD after 1 year were optimized. Conclusions: In this study, we tested the hypothesis that people with elevated body T after initial ZOL treatment had greater improvements in BMD and better outcomes. Trial registration: NCT, NCT03158246. Registered 18/05/2017. [ABSTRACT FROM AUTHOR]

Background: This study attempted to evaluate clinically and histologically the effect of local injection of transforming growth factor beta 1 (TGFβ1) on the rate of orthodontic relapse. Methods: 24 male albino rabbits were used, that grouped randomly into two groups (12 rabbits in each): positive control and TGFβ1 groups. Each group was further divided into 3 subgroups with 4 rabbits in each. Modified orthodontic appliances were cemented to the mandibular central incisors and tooth movement was carried out for 2 weeks, followed by a retention period for 3 weeks where positive control and TGFβ1 groups received local injections of phosphate buffer saline and TGFβ1 solutions, respectively, then the teeth allowed to relapse after removing the appliances for 20 days. The relapse was estimated clinically. Histological and immunohistochemical analyses were carried out following the completion of the experiment. Result: The TGFβ1 group showed a significantly lower rate of relapse than the positive control group. Histologically, during the relapse period, a significant increase in the number of osteoblasts, a decrease in the number of osteoclast, which was also confirmed by immunohistochemical analyses and a lesser PDL width was seen in TGFβ1 group when compared to the positive control group. local injection of TGFβ1 can significantly reduce the orthodontic relapse in the rabbit model. [ABSTRACT FROM AUTHOR]

Harris lines (HLs) are radiographically visible transverse lines of thickened bone that develop from temporary growth cessation during early life. Often attributed to physiological stress during development, HLs are frequently observed in the long bones of adolescents and become less visible over time due to bone remodeling. In recent years, the validity of HL as a sign of stress has been called into question and the methods used in studying HL through X‐ray analysis scrutinized. In this study, 80 individuals from the Middle Holocene Cis‐Baikal region of Siberia, from the Early Neolithic (EN; 7560–6660 HPD cal. BP) and Late Neolithic (LN; 6060–4970 HPD cal. BP), were studied for the presence and severity of HL. Radiographic analysis employed both the traditional clinical anteroposterior (A–P) orientation and a potentially improved mediolateral (M–L) orientation. EN groups in the Cis‐Baikal are known to have experienced higher levels than their LN counterparts; thus, if HL reflect stress experiences, we expected to see more HL in the EN population compared with the LN population. We also expected more visible HL in the M–L orientation due to the suggested improvement in capturing more lines compared with the A–P orientation. While the results support the use of M–L orientation during X‐ray capture of HL, there was not a higher number of HL in the EN population as expected. Instead, no significant differences were found in HL severity between the EN and LN populations, and age‐at‐death resulted in a greater effect on HL counts regardless of mortuary site. The results from this study align not with known stress data from the Middle Holocene Cis‐Baikal populations but rather with data pertaining to known growth patterns. We therefore advocate against the use of HL as a sign of physiological stress and instead suggest HL as a reflection of bone growth trajectory. [ABSTRACT FROM AUTHOR]

Objective: To develop multiplex cytokine detection reagents to analyze expression levels of cytokines, angiogene sis and bone remodeling proteins in relapse/refractory multiple myeloma (RRMM) . Methods: Multiplex bead-based immunoassay by flow cytometry was used to develop quantitative detection reagents of multiplex cytokines, which were applied to detect serum samples from 55 RRMM patients and 22 healthy controls. Expression levels of cytokines, angiogenesis, and bone remodeling proteins in pa tients, and their correlation with clinical characteristics were analyzed. Results: Detection reagents of 10-plex cytokine immunoassay were successfully developed in this study, with average sensitivity of 7.1 pg/ml, average recovery rate of 97.4%, average intra-assay CV of 4.8%, and average inter-assay CV of 9.0%. In addition, results of RRMM samples found that levels of IL-2, IL-17, DKK1, RANKL and OPG were positively correlated with the level of IgG monoclonal protein, and TIMP1 was positively correlated with levels of IgG and IgA monoclonal protein. Conclusion: In this study, ten kinds of cytokine detection reagents with high sensitivity and speci ficity are developed, and we found that IL-2, IL-17, DKK1, RANKL, OPG and TIMP1 have potential value in tracking disease pro gression in RRMM. The established development process of multiplex cytokine reagents has important reference significance for expanding the development and application of multiplex detection reagents for protein markers in the future. [ABSTRACT FROM AUTHOR]

Osseodensification enhances the stability of endosteal implants. However, pre-clinical studies utilizing osseodensification instrumentation do not account for the limited presence of trabeculae seen clinically. This study aimed to evaluate the effect of osseodensification instrumentation on osteotomy healing in scenarios with and without the presence of trabecular bone. A ~10 cm incision was made over the hip of twelve sheep. Trabecular bone was surgically removed from twelve sites (one site/animal; negative control (Neg. Ctrl)) and left intact at twelve sites (one site/animal; experimental group (Exp.)). All osteotomies were created using the osseodensification drilling protocol. Each osteotomy received an endosteal implant and was evaluated after 3 or 12 weeks of healing (n = 6 animals/time). Histology revealed increased woven and lamellar bone surrounding the implants in the Exp. group relative to the Neg. Ctrl group. The Exp. group demonstrated the presence of bone fragments, which acted as nucleating sites, thereby enhancing the bone formation and remodeling processes. Bone-to-implant contact (%BIC) and bone area fractional occupancy (%BAFO) were significantly higher in the Exp. group relative to the Neg. Ctrl group both at 3 weeks (p = 0.009 and p = 0.043) and 12 weeks (p = 0.010 and p = 0.008). Osseodensification instrumentation in the presence of trabecular bone significantly improved osseointegration. However, no negative influences such as necrosis, inflammation, microfractures, or dehiscence were observed in the absence/limited presence of trabeculae. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up. [ABSTRACT FROM AUTHOR]

Mesoporous calcium phosphate based-bioceramics with ionic substitution have attracted attention for treatment of bone diseases and bone regeneration. Carbonate apatite (CO3Ap) is a promising candidate for bone replacement through bone remodelling, similar to that of autologous bone, owing to the chemical composition of the bone mineral. In this work, we present a dual approach to synthesize mesoporous carbonate apatite (CO3Ap) and strontium-substituted CO3Ap (Sr-CO3Ap) artificial bone nanocrystals, aiming to assess the impact of strontium on CO3Ap characteristics and biological performance. Mesoporous CO3Ap was created by transforming hard templates composed of CaCO3, while Sr-substituted CaCO3 (Sr-CaCO3) microspheres were formed using an organic complexing agent to induce pore formation. The resulting CO3Ap and Sr-CO3Ap granules exhibited an irregular shape, with rod-like nanocrystals composing their particles. Adsorption/desorption isotherms confirmed the mesoporous nature of the structures, featuring pore sizes ranging from 10 to 50 nm. Specifically, mesoporous CO3Ap displayed slit-like pores, while Sr-CO3Ap showed cylinder-like ones. High-resolution transmission electron microscopy images of Sr-CO3Ap powder revealed mesopores within the particles, with Sr-CO3Ap exhibiting larger pore volume and specific surface area compared to CO3Ap. When osteoblast-like MC3T3-E1 cells were cultured on both CO3Ap and Sr-CO3Ap samples, they demonstrated good cell attachment, proliferation rates, and increased ALP activity, particularly evident at higher strontium concentrations. These findings suggest promising potential for further exploration of mesoporous apatite nanocrystals in bone replacement and drug delivery applications. [ABSTRACT FROM AUTHOR]

Background: Bone regeneration is a well‐regulated dynamic process, of which the prominent role of the immune system on bone homeostasis is more and more revealed by recent research. Before fully activation of the bone remodeling cells, the immune system needs to clean up the microenvironment in facilitating the bone repair initiation. Furthermore, this microenvironment must be maintained properly by various mechanisms over the entire bone regeneration process. Objective: This review aims to summarize the role of the T‐helper 17/Regulatory T cell (Th17/Treg) balance in bone cell remodeling and discuss the relevant progress in bone tissue engineering. Results: The role of the immune response in the early stages of bone regeneration is crucial, especially the impact of the Th17/Treg balance on osteoclasts, mesenchymal stem cells (MSCs), and osteoblasts activity. By virtue of these knowledge advancements, innovative approaches in bone tissue engineering, such as nano‐structures, hydrogel, and exosomes, are designed to influence the Th17/Treg balance and thereby augment bone repair and regeneration. Conclusion: Targeting the Th17/Treg balance is a promising innovative strategy for developing new treatments to enhance bone regeneration, thus offering potential breakthroughs in bone injury clinics. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Paget's disease of bone (PDB) is a chronic condition causing abnormal bone remodeling, leading to pain, fractures, and complications. A 57‐year‐old female patient, asymptomatic and devoid of pain, incidentally exhibited elevated levels of alkaline phosphatase. Following a thorough consideration of potential differential diagnoses, the eventual diagnosis established was PDB. We recommended Fosamax (70 mg alendronate tablets) at two tablets twice weekly for 3 months to manage PDB due to patient preference and side effects with intravenous zoledronic acid. Subsequent assessments of alkaline phosphatase levels during follow‐up examinations post‐treatment revealed a reduction in their values. [ABSTRACT FROM AUTHOR]

Despite therapy with growth hormone (GH) in children with Prader–Willi syndrome (PWS), low bone mineral density and various orthopedic deformities have been observed often. Therefore, this study aimed to analyze bone markers, with an emphasis on vitamin K-dependent proteins (VKDPs), in normal-weight children with PWS undergoing GH therapy and a low-energy dietary intervention. Twenty-four children with PWS and 30 healthy children of the same age were included. Serum concentrations of bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), periostin, osteopontin, osteoprotegerin (OPG), sclerostin, C-terminal telopeptide of type I collagen (CTX-I), and insulin-like growth factor-I (IGF-I) were determined using immunoenzymatic methods. OC levels and the OC/CTX-I ratios were lower in children with PWS than in healthy children (p = 0.011, p = 0.006, respectively). Glu-OC concentrations were lower (p = 0.002), but Gla-OC and periostin concentrations were higher in patients with PWS compared with the controls (p = 0.005, p < 0.001, respectively). The relationships between IGF-I and OC (p = 0.013), Gla-OC (p = 0.042), and the OC/CTX-I ratio (p = 0.017) were significant after adjusting for age in children with PWS. Bone turnover disorders in children with PWS may result from impaired bone formation due to the lower concentrations of OC and the OC/CTX-I ratio. The altered profile of OC forms with elevated periostin concentrations may indicate more intensive carboxylation processes of VKDPs in these patients. The detailed relationships between the GH/IGF-I axis and bone metabolism markers, particularly VKDPs, in children with PWS requires further research. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate whether the biomarkers for bone turnover could rapidly recover during the period of diabetic ketoacidosis (DKA). Bone turnover biomarkers, including 25-hydroxyvitamin D3, N-terminal middle molecular fragment of osteocalcin (NMID), and β-C terminal cross-linking telopeptide of type 1 collagen were evaluated using in-patient data (n=627) from Shanghai Pudong Hospital from 2018–2022. The comparison was performed between type 2 diabetes (T2D only) (n=602) and DKA (n=25), in which we checked the bone turnover markers at pre-treatment and recovery. After matching by body mass index (BMI), we found that except for 25-OH-VitD3, the age difference, indices of glucose metabolism, and bone turnover were significant between the 2 groups (p<0.05). We found only a significant restoration of NMID (p<0.001). NMID and β-CTX, when compared with T2D, showed overt distinction between recovery and T2D (p<0.05). In addition, the investigations demonstrated a substantial difference between 25-OH-VitD3 in males and NMID in females, regardless of age (p<0.05). Multilinear regression analysis revealed that 2 hours postprandial plasma C-peptide was an independent predictor of the NMID in both pre-treatment (β=0.58, p=0.003) and recovery (β=0.447, p=0.025), although sex was significant in pre-treatment (β=–0.444, p=0.020). Finally, we found that only age variation affected DKA's fasting plasma glucose level (p<0.05). The study revealed that the bone turnover of DKA is significantly different in pre-treatment and recovery; however, NMID might recover quickly if the patients received appropriate treatment. Importantly, pancreatic function plays a critical role in changing bone turnover biomarkers. [ABSTRACT FROM AUTHOR]

Objectives: The present study aimed to investigate the effectiveness of treatment with romosozumab for 1 year and association between bone turnover markers and changes in bone mineral density (BMD) in patients with postmenopausal osteoporosis. Methods: Participants were 53 treatment-naïve postmenopausal osteoporosis patients. Correlations of per cent changes (Δ) in lumbar (L) and total hip (TH) BMD 12 months after initiating romosozumab with baseline demographic factors and parameters of N-terminal propeptide of Type 1 collagen (P1NP) and tartrate-resistant acid phosphatase-5b at baseline and Months 1, 3, and 6 were assessed. Multiple regression analysis was performed on factors significantly correlated with ΔL-BMD and ΔTH-BMD at Month 12. Results: ΔL-BMD and ΔTH-BMD at Month 12 were 17.5% and 8.1%, respectively. Multiple regression analysis revealed that a high P1NP value at Month 3 predicted large increases in L-BMD and TH-BMD at Month 12. High total amount of P1NP values from baseline to Month 6 was associated with large increases in L-BMD and TH-BMD at Month 12 and was most strongly correlated with the P1NP value at Month 3. Conclusions: A high P1NP value at Month 3 predicted large increases in both L-BMD and TH-BMD at Month 12 in postmenopausal osteoporosis patients treated with romosozumab. [ABSTRACT FROM AUTHOR]

This study investigated the effect of 4 days low energy availability (LEA) on physiological markers and mood states in male endurance runners. Twelve participants (mean (standard deviation); age: 25.8 (3.8) years; fat-free mass (FFM): 52.8 (5.5) kg) completed three 4-day conditions: adequate energy availability (AEA): 45 kcal/kg FFM/day; LEA1: 30 kcal/kg FFM/day; and LEA2: 15 kcal/kg FFM/day, in a randomized order. Participants ran on a treadmill at 65% of V̇O2max until they expended 15 kcal/kg FFM/day of energy. Energy intake was adjusted to achieve the desired energy availability. Pre- and post-measurements of bone turnover, metabolism, testosterone and estradiol (plasma), resting metabolic rate (indirect calorimetry), and mood states (Brunel Mood Scale) were assessed. The results reported a significant decrease in testosterone (condition × time interaction, p = 0.03) occurred on LEA2 (Pre: 23.8 (7.0) nmol/L vs. Post: 20.3 (7.7) nmol/L) compared with AEA (Pre: 22.9 (5.5) nmol/L vs. Post: 23.3 (6.1) nmol/L) or LEA1 (Pre: 23.6 (8.6) nmol/L vs. Post: 20.9 (8.8) nmol/L). Fatigue level significantly increased (condition × time interaction, p = 0.02) in LEA2 (Pre: 3.5 (1.7) vs. Post: 6.5 (2.9)) but did not change in AEA (Pre: 2.8 (1.5) vs. Post: 2.5 (2.7)) or LEA1 (Pre: 2.8(2.4) vs. Post: 2.9 (2.0)). Other measures were unaffected by the interventions. In conclusion, this study suggests that testosterone and fatigue may serve as early indicators of LEA in male runners. However, other physiological markers and mood states appeared largely unaffected, aligning with existing literature indicating minimal disruption of physiological functions during acute LEA in male athletes. Study registration: Australian New Zealand Clinical Trials Registry (Trial No.: 381278). [ABSTRACT FROM AUTHOR]

Osteoporosis and sarcopenia are both common age-related disorders that are associated with increased morbidity and mortality. Bone and muscle are metabolically very active tissues that require large amounts of energy. Bile acids (BAs), a group of liver-derived steroid compounds, are primarily known as emulsifiers that facilitate the resorption of dietary fat and lipids. In addition, they have pleiotropic metabolic functions in lipoprotein and glucose metabolism, inflammation, and intestinal bacterial growth. Through these effects, they are related to metabolic diseases, such as diabetes, hypertriglyceridemia, atherosclerosis, and nonalcoholic steatohepatitis. BAs mediate their metabolic effects through receptor dependent and receptor-independent mechanisms. Emerging evidence suggests that BAs are also involved in bone and muscle metabolism. Under normal circumstances, BAs support bone health by shifting the delicate equilibrium of bone turnover toward bone formation. In contrast, low or excessive amounts of BAs promote bone resorption. In cholestatic liver disease, BAs accumulate in the liver, reach toxic concentrations in the circulation, and thus may contribute to bone loss and muscle wasting. In addition, the measurement of BAs is in rapid evolution with modern mass spectrometry techniques that allow for the detection of a continuously growing number of BAs. This review provides a comprehensive overview of the biochemistry, physiology and measurement of bile acids. Furthermore, it summarizes the existing literature regarding their role in bone and muscle. [ABSTRACT FROM AUTHOR]

Vascular calcification affects the prognosis of patients with renal failure. Bisphosphonates are regarded as candidate anti-calcifying drugs because of their inhibitory effects on both calcium-phosphate aggregation and bone resorption. However, calcification in well-known rodent models is dependent upon bone resorption accompanied by excessive bone turnover, making it difficult to estimate accurately the anti-calcifying potential of drugs. Therefore, models with low bone resorption are required to extrapolate anti-calcifying effects to humans. Three bisphosphonates (etidronate, alendronate, and FYB-931) were characterised for their inhibitory effects on bone resorption in vivo and calcium-phosphate aggregation estimated by calciprotein particle formation in vitro. Then, their effects were examined using two models inducing ectopic calcification: the site where lead acetate was subcutaneously injected into mice and the transplanted, aorta obtained from a donor rat. The inhibitory effects of bisphosphonates on bone resorption and calcium-phosphate aggregation were alendronate > FYB-931 > etidronate and FYB-931 > alendronate = etidronate, respectively. In the lead acetate-induced model, calcification was most potently suppressed by FYB-931, followed by alendronate and etidronate. In the aorta-transplanted model, only FYB-931 suppressed calcification at a high dose. In both the models, no correlation was observed between calcification and bone resorption marker, tartrate-resistant acid phosphatase (TRACP). Results from the lead acetate-induced model showed that inhibitory potency against calcium-phosphate aggregation contributed to calcification inhibition. The two calcification models, especially the lead acetate-induced model, may be ideal for the extrapolation of calcifying response to humans because of calcium-phosphate aggregation rather than bone resorption as its mechanism. [ABSTRACT FROM AUTHOR]

To explore serum levels of some bone turnover markers and the involvement of the Wnt signaling in CRPS-1. Query ID="Q1" Text="Please check and confirm whether the edit made to the article title is in order." We conducted an observational study on patients with early CRPS-1 recruited before any treatment. Clinical measures were assessed together with biochemical evaluation. Values of sclerostin, DKK1, CTX-I, and P1NP were compared with sex-age-matched healthy controls (HCs). We enrolled 34 patients diagnosed with CRPS-1 (mean age 59.3 ± 10.6 years, Male/Female 10/24), median disease duration = 2 weeks (IQR 1–5); median VAS score = 76 (IQR 68–80). Foot localization was slightly more frequent than hand localization (18/16). No statistically significant difference was found between CRPS-1 patients and HCs for CTX-I (0.3 ± 0.1 ng/ml vs 0.3 ± 0.1, p = 0.140), while mean serum values of P1NP were significantly higher in CRPS-1 patients compared to HCs (70.0 ± 38.8 ng/ml vs 50.1 ± 13.6, p = 0.005). Mean levels of sclerostin and DKK1 were lower in CRPS-1 patients vs HCs (sclerostin 28.4 ± 10.8 pmol/l vs 34.1 ± 11.6, p = 0.004; DKK1 12.9 ± 10.8 pmol/l vs 24.1 ± 11.9, p = 0.001). No statistically significant difference was found for all biochemical assessments in a subgroup of fracture-induced CRPS-1. No statistically significant differences were observed according to disease localization, disease duration, presence of hyperalgesia, allodynia, sudomotor alterations, and mild or moderate/severe swelling. No significant correlation emerged between sclerostin, DKK1 levels, baseline VAS score, or McGill Pain Questionnaire score. Bone involvement in early CRPS-1 does not seem to rely on increased osteoclast activity. Conversely, a serum marker of bone formation resulted increased. Both Sclerostin and DKK1 showed decreased values, probably suggesting a widespread osteocyte loss of function. Trial registration number: Eudract Number: 2014-001156-28 [ABSTRACT FROM AUTHOR]

Context Current osteoporosis pharmacological treatment has undesirable side effects. There is increasing focus on naturally derived food substances that contain phytonutrients with antioxidant effects in promoting health and regulating immune response. Objective This review aims to systematically evaluate the effectiveness of anthocyanin-rich foods on bone remodeling biomarkers in middle-aged and older adults (≥40 y old) at risk of osteoporosis. Data Sources Randomized controlled trials were searched on 8 bibliographic databases of PubMed, Embase, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Food Science and Technology Abstracts, Cochrane Library, and ProQuest. Data Extraction and Analysis Thirteen studies were included in the meta-analysis. Receptor activator of nuclear factor kappa-B ligand (RANKL) is exhibited from osteoblastic cells that gathered osteoclasts to bone sites for bone resorption, accelerating bone loss. Anthocyanin-rich food consumption showed statistically nonsignificant effects, with no substantial heterogeneity on bone remodeling biomarkers. However, there was a significant increase in lumbar spine L1–L4 bone mineral density. Mild-to-small effects were seen to largely favor the consumption of anthocyanin-rich foods. Berries (d = –0.44) have a larger effect size of RANKL than plums (d = 0.18), with statistically significant subgroup differences. Random-effects meta-regression found body mass index, total attrition rate, total energy, and dietary carbohydrate and fat intake were significant covariates for the effect size of RANKL. All outcomes had low certainty of evidence. Conclusion Anthocyanin-rich foods may improve bone health in middle-aged and older adults at risk of osteoporosis. This review contributes to the growing interest in nutrient-rich foods as a low-cost and modifiable alternative to promote human health and reduce disease burden. Future high-quality studies with larger sample sizes and longer treatment durations are required to fully understand the effect of anthocyanin-rich foods on bone health. Systematic Review Registration PROSPERO registration no. CRD42022367136. [ABSTRACT FROM AUTHOR]

In the pathogenesis of osteoarthritis, various signaling pathways may influence the bone joint through a common terminal pathway, thereby contributing to the pathological remodeling of the joint. Semaphorins (SEMAs) are cell-surface proteins actively involved in and primarily responsible for regulating chondrocyte function in the pathophysiological process of osteoarthritis (OA). The significance of the SEMA family in OA is increasingly acknowledged as pivotal. This review aims to summarize the mechanisms through which different members of the SEMA family impact various structures within joints. The findings indicate that SEMA3A and SEMA4D are particularly relevant to OA, as they participate in cartilage injury, subchondral bone remodeling, or synovitis. Additionally, other elements such as SEMA4A and SEMA5A may also contribute to the onset and progression of OA by affecting different components of the bone and joint. The mentioned mechanisms demonstrate the indispensable role of SEMA family members in OA, although the detailed mechanisms still require further exploration. [ABSTRACT FROM AUTHOR]

Summary: Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. Purpose: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. Methods: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. Results: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. Conclusion: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF. [ABSTRACT FROM AUTHOR]

Rationale: Patients with schizophrenia with second-generation antipsychotics (SGAs) treatment have shown an increased risk of bone fragility and susceptibility to fracture; however, it is still unclear whether this risk is derived from the effect of antipsychotics on balance of bone metabolism. Objectives: We investigated the changes of two bone turnover biomarkers (BTMs) concentrations in people with schizophrenia receiving SGAs: procollagen type I aminoterminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX-1) as BTMs of osteogenesis and bone resorption, respectively, to explore how antipsychotics contribute to bone fragility. Methods: We recruited 59 Chinese male patients with schizophrenia (32 drug-naïve first-episode (DNFE) patients and 27 chronic patients) to undergo 8 weeks SGAs treatment. Fasting peripheral blood samples of pre- and posttreatment were collected, plasma levels of PINP and CTX-1 were measured. Results: The interaction effects of group and time on PINP and CTX-1 concentrations were found (P =.016 and P =.008). There was a significant decrease for both BTMs concentrations of the posttreatment compared to the pretreatment (P<.001 and P =.003). Chronic patients had significantly higher changes of BTMs concentrations compared to DNFE patients (P =.048 and P =.024). There was a positive correlation of the two BTMs of pretreatment with disease course in DNFE group (r =.37, P =.039;r =.38, P =.035) and a negative correlation of PINP of pretreatment with age in the chronic group (r=-.40, P =.039). Conclusion: Long-term SGAs medication inhibited osteogenesis in a dose- and time-dependent manner and damaged the balance of bone formation and bone resorption. [ABSTRACT FROM AUTHOR]

The opioid epidemic is a public health crisis affecting spine care and pain management. Medical marijuana is a potential nonopioid analgesic yet to be studied in the surgical setting since its effects on bone healing are not fully understood. Studies have demonstrated analgesic and potentially osteoinductive properties of cannabinoids with endocannabinoid receptor expression in bone tissue. We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion. Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4–L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1 ml intraperitoneal injections weekly as follows: placebo (saline), 5 mg/kg THC, 5 mg/kg CBD, and a combination of 5 mg/kg THC and 5mg/kg CBD (Combo). Callus tissue was harvested 2- and 8-weeks postsurgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4–L5 arthrodesis on all rats. μCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed. μCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at 2 weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (p>.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points. This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at 2 weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases. CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the postoperative setting following spinal fusions. [ABSTRACT FROM AUTHOR]

Bone resorption follows a circadian rhythm, with a marked reduction in circulating markers of resorption (such as carboxy-terminal telopeptide region of collagen type I in serum) in the postprandial period. Several gut hormones, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2, have been linked to this effect in humans and rodent models. These hormones are secreted from enteroendocrine cells in the gastrointestinal tract in response to a variety of stimuli and effect a wide range of physiological processes within and outside the gut. Single GLP1, dual GLP1–GIP or GLP1–glucagon and triple GLP1–GIP–glucagon receptor agonists have been developed for the treatment of type 2 diabetes mellitus and obesity. In addition, single GIP, GLP1 and GLP2 analogues have been investigated in preclinical studies as novel therapeutics to improve bone strength in bone fragility disorders. Dual GIP–GLP2 analogues have been developed that show therapeutic promise for bone fragility in preclinical studies and seem to exert considerable activity at the bone material level. This Review summarizes the evidence of the action of gut hormones on bone homeostasis and physiology. This Review summarizes the evidence regarding the actions of gut hormones on bone homeostasis and physiology. The potential implications for the development of future therapeutics to treat bone fragility are considered. Key points: Circulating markers of bone resorption, and to a lesser extent bone formation, follow a circadian pattern, with a notable reduction occurring in humans during the postprandial period. Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2 modulate circulating markers of bone resorption during the postprandial period in humans. In humans and rodents, GIP–GIP receptor and GLP2–GLP2 receptor have distinct but additive effects on bone turnover and bone material properties, including enhanced enzymatic collagen crosslinking. In rodents, single analogues of GIP, GLP1 and GLP2 improve bone density, microstructure and material properties. In rodent models of bone fragility, dual GIP–GLP2 analogues improve bone strength by acting at the bone material level. [ABSTRACT FROM AUTHOR]

Oxygen (O 2)-delivering tissue substitutes have shown tremendous potential for enhancing tissue regeneration, maturation, and healing. As O 2 is both a metabolite and powerful signaling molecule, providing controlled delivery is crucial for optimizing its beneficial effects in the treatment of critical-sized injuries. Here, we report the design and fabrication of 3D-printed, biodegradable, O 2 -generating bone scaffold comprising calcium peroxide (CPO) that once hydrolytically activated, provides long-term generation of oxygen at a controlled, concentration-dependent manner, and polycaprolactone (PCL), a hydrophobic polymer that regulate the interaction of CPO with water, preventing burst release of O 2 at early time points. When anoxic conditions were simulated in vitro , CPO-PCL scaffolds maintained the survival and proliferation of human adipose-derived stem/stromal cells (hASCs) relative to PCL-only controls. We assessed the in vivo osteogenic efficacy of hASC-seeded CPO-PCL scaffolds implanted in a non-healing critical-sized 4-mm calvarial defects in nude mice for 8 weeks. Even without exogenous osteoinductive factors, CPO-PCL scaffolds demonstrated increased new bone volume compared to PCL-only scaffolds as verified by both microcomputed tomography analysis and histological assessments. Lastly, we employed a quantitative 3D lightsheet microscopy platform to determine that O 2 -generating scaffolds had similar vascular volumes with slightly higher presence of CD31hiEmcnhi pro-osteogenic, type H vessels and increased number of Osterix+ skeletal progenitor cells relative to PCL-only scaffolds. In summary, 3D-printed O 2 generating CPO-PCL scaffolds with tunable O 2 release rates provide a facile, customizable strategy for effectively treating, craniofacial bone defects. Oxygen(O 2)-delivering bone substitutes show promise in defect repair applications by supplying O 2 to the cells within or around the graft, improving cell survivability and enhancing bone matrix mineralization. A novel O 2 -generating bone scaffold has been 3D printed for the first-time which ensures patient and defect specificity. 3D printed calcium peroxide-polycaprolactone (CPO-PCL) bone scaffold provides uninterrupted O 2 supply for 22 days allowing cell survival in deprived O 2 and nutrient conditions. For the first time, O 2 -driven bone regenerative environment in mice calvaria has been captured by light-sheet imaging which illuminates abundance of Osterix+ cells, angiogenesis at a single cell resolution indicating active site of bone remodeling and growth in the presence of O 2. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: Glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) may promote bone formation, but conversely, they could also weaken bones due to the reduction in mechanical load associated with weight loss. However, the clinical effects in humans have not been clearly demonstrated. This meta‐analysis aimed to evaluate whether GLP‐1RAs affect BMD and bone turnover markers. Material and Methods: PubMed, Embase, and Scopus were searched on June 13, 2024. The eligibility criteria were: (1) human studies, (2) receiving a GLP‐1RA for more than 4 weeks, (3) an untreated control group or a placebo group, (4) reporting of at least one BMD or bone turnover marker, and (5) an RCT design. The risk of bias was assessed using the Cochrane risk of bias 2 tool. Fixed‐ or random‐effects meta‐analysis was performed according to heterogeneity. Results: Seven studies were included in the meta‐analysis. GLP‐1RAs did not significantly change BMD in the femoral neck (mean difference [MD], 0.01 g/cm2; 95% CI, −0.01–0.04 g/cm2), in the total hip (MD, −0.01 g/cm2; 95% CI, −0.02–0.01 g/cm2), and in the lumbar spine (MD, 0 g/cm2; 95% CI, −0.02–0.02 g/cm2). C‐terminal telopeptide of type 1 collagen (CTX), a bone resorption marker, significantly increased after GLP‐1RA treatment (MD, 0.04 μg/L; 95% CI, 0.01–0.07 μg/L). GLP‐1RAs did not significantly change bone formation markers such as procollagen type 1 N‐terminal propeptide, bone‐specific alkaline phosphatase, osteocalcin. Conclusions: GLP‐1RA did not affect BMD and bone formation markers. However, GLP‐1RAs led to a significant increase in CTX. [ABSTRACT FROM AUTHOR]

Bone tissue is subjected to increased mechanical stress during high-intensity work. Inadequate bone remodeling reparability can result in the continuous accumulation of microdamage, leading to stress fractures. The aim of this work was to investigate the characteristics and repair mechanisms of tibial microdamage under several degrees of overload. Also, we aimed at better understanding the effects of overload on the multi-scale structure and mechanical properties of bone. Sixty 5-month female rats were divided into three groups with different time points. Micro-CT was used to evaluate the three-dimensional microstructure, and three-point bending, quasi-static fracture toughness and creep mechanical test were carried out to evaluate the mechanical properties. SEM was used to observe the morphological characteristics of fracture surfaces. Section staining was used to count the microdamage parameters and numbers of osteoblasts and osteoclasts. The microarchitectures of cancellous and cortical bones in the three overload groups showed different degrees of damage. Overload led to a messy crystal structure of cortical bone, with slender microcracks mixed in, and a large number of broken fibers of cancellous bone. The properties associated with the elastic plasticity, fracture toughness, and viscoelasticity of cortical bone reduced in three groups, with that corresponding to day 30 presenting the highest damage. The accumulation of microdamage mainly occurred in the first 14 days, that is, the crack density peaked on day 14. Peak-targeted bone remodeling of cortical and cancellous bones occurred mainly between days 14 and 30. The influence of overload mechanical environment on bone quality at different time points was deeply investigated, which is of great significance for the etiology and treatment of stress fractures. [ABSTRACT FROM AUTHOR]

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. Lay Summary: Radiation therapy (RT) for rectal cancer before surgery reduces the risk of cancer recurrence, but can cause injuries to the pelvic bone. Despite the high morbidity from RT-caused skeletal injuries, predictive and preventive measures are lacking. How these bone injuries are reflected by bone biomarkers measured in serum is largely unknown. The aim of this study was to measure serum bone biomarkers and their relation to RT-related bone injuries in women with rectal cancer. The study group included 47 women with rectal cancer treated with surgery ± preoperative RT. Pelvic magnetic resonance imaging was used for detection of skeletal injury. The bone biomarkers 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 after surgery. Sixteen of 36 (44%) irradiated women had radiation-caused bone injuries and were compared to 31 women without bone injuries. Serum CTX, BALP, and PINP increased during the first year after RT in women with radiation-caused bone injuries. In summary, bone markers may be of interest for future research on fracture prediction or preventive measures in women prone to radiation-caused bone injury. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective cohort study Objectives: The criteria for determining completion of intervertebral stability after posterior lumbar interbody fusion (PLIF) remain controversial. Several new radiological indicators of bone growth and osteointegration have been established. We compared computed tomography (CT) findings related to osteointegration after PLIF with interbody cages of two different materials and designs. Methods: We retrospectively analyzed data from 103 patients who underwent PLIF with three-dimensional porous tantalum (Tn) cages or titanium-coated polyetheretherketone (TiP) cages. CT images obtained 3 months and 1 year after surgery were examined for trabecular bone remodeling (TBR), cancellous condensation (CC), and vertebral endplate cyst (VEC) formation. The incidences of each finding were compared by cage type, and rates of instrument failure and pseudarthrosis were determined. Results: Three months postoperatively, 87% of the levels with Tn cages exhibited TBR, whereas 96% of those with TiP cages did not (P <.001). Most levels with Tn cages levels exhibited TBR and no CC 3 months (81%) and 1 year (94%) after surgery. Although 78% of levels with TiP cages exhibited CC and no TBR 3 months after surgery, 59% exhibited both CC and TBR 1 year after surgery. Significantly fewer VECs formed around the Tn cages than around the TiP cages both 3 months (P =.002) and 1 year (P <.001) after surgery. Implant-related problems occurred at levels that exhibited neither TBR nor CC. Conclusions: The porous tantalum cage may enable intervertebral stability that is comparable to bony fusion soon after surgery. [ABSTRACT FROM AUTHOR]

This study aimed to demonstrate whether impregnating the graft bone with platelet-rich plasma (PRP) accelerates graft bone catabolism in lateral lumbar interbody fusion (LLIF). Consecutive patients who underwent LLIF were assessed. Of the two spaces for bone grafts in the intervertebral cage, one space was filled with graft bone impregnated with PRP, and the other was filled with graft bone without PRP, which divided the graft bones into PRP and non-PRP groups. The mean Hounsfield units (HU) of the graft bone at the center of the cage space in the coronal and axial slices were measured using computed tomography (CT) images 1 week and 6 months after surgery. The delta value of HU from 1 week to 6 months after surgery was calculated for the PRP and non-PRP groups. We compared the delta values of the HU between the two groups. The PRP and non-PRP groups comprised 16 bone grafts. In the coronal slices, the HU value in the PRP group (delta value: 526.1 ± 352.2) tended to have a greater decrease at 6 months after surgery compared with that in the non-PRP group (delta value: 217.6 ± 240.4) (p = 0.065). In the axial slices, the HU value in the PRP group (delta value: 501.3 ± 319.6) was significantly decreased at 6 months after surgery compared with that in the non-PRP group (delta value: 159.2 ± 215.3) (p = 0.028). Impregnating the graft-bone with PRP accelerated graft bone catabolism in LLIF within 6 months after surgery. [ABSTRACT FROM AUTHOR]

Alveolar bone remodeling during the retention phase is essential for successful orthodontic treatment. Pulsed electromagnetic field (PEMF) therapy is an adjunctive therapy for bone-related diseases that induces osteogenesis and prevents bone loss. This study aimed to examine the role of PEMF exposure during the retention phase of orthodontic treatment in alveolar bone remodeling. A total of 36 male Wistar rats were divided into control, PEMF 7, and PEMF 14 groups; a 50 g force nickel–titanium closed-coil spring was inserted to create mesial movement in the first molar for 21 d. Furthermore, the spring was removed, and the interdental space was filled with glass ionomer cement. Concurrently, rats were exposed to a PEMF at 15 Hz with a maximum intensity of 2.0 mT 2 h daily, for 7 and 14 days. Afterwards, the cements were removed and the rats were euthanized on days 1, 3, 7, and 14 to evaluate the expression of Wnt5a mRNA and the levels of RANKL, OPG, ALP, and Runx2 on the tension side. The data were analyzed with ANOVA and post hoc tests, with p < 0.05 declared statistically significant. PEMF exposure significantly upregulated Wnt5a mRNA expression, OPG and ALP levels, and Runx2 expression, and decreased RANKL levels in the PEMF 7 and 14 groups compared to the control group (p < 0.05). This study showed that PEMF exposure promotes alveolar bone remodeling during the orthodontic retention phase on the tension side by increasing alveolar bone formation and inhibiting resorption. [ABSTRACT FROM AUTHOR]

This study aimed to establish the preparation process of peptide–calcium chelates (TMP-Ca) using skipjack tuna meat and investigate the function and mechanism of TMP-Ca in an osteoporosis model of rats. The results indicated that trypsin is more suitable for preparing the Ca-chelating hydrolysates of tuna meat, and the optimal hydrolysis conditions were derived as follows: digestion time 4 h, material–liquid ratio 1:10, and enzyme dose 3%. The conditions for chelating Ca with tuna meat hydrolysate were optimized to be chelation time 50 min, temperature 50 °C, pH 8.0, and a peptide–Ca ratio 1:10. The prepared hydrolysate was subjected to ultrafiltration, and the fraction (TMP) (MW <1 kDa) showed the highest Ca chelation rate (51.27 ± 1.42%) and was made into the peptide–Ca chelates (TMP-Ca). In osteoporotic rats, TMP-Ca significantly improved the decrease in ovarian indexes caused by retinoic acid. It also elevated serum Ca, phosphorus, and bone turnover indexes, increased the number of bone trabeculae, and improved bone microstructure. In addition, we confirmed that TMP-Ca could regulate the OPG/TRAF6 pathway to reduce osteoclast differentiation, inhibit bone resorption, and promote bone formation. Therefore, TMP-Ca could significantly ameliorate osteoporosis, and this study provides a functional component for the preparation of healthcare products using skipjack tuna meat to treat osteoporosis. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (KOA) is a serious public health concern and is described as a disorder characterised by degradation of articular cartilage, bone remodeling and inflammation, leading to pain, stiffness and functional impairment, primarily affecting weight bearing joints and hands. KOA affects more than 650 million individuals worldwide and is a leading cause of disability. In India, 28.7% of adults ≥ 40 years of age and 45.5% of adults ≥ 60 years of age have KOA. The annual incidence rate of KOA in India is 2.4%. The management of KOA involves a comprehensive approach, including non-pharmacological management, pharmacological management, surgical management, alternative therapies and lifestyle changes. By combining these management strategies, individuals with KOA can effectively reduce pain, improve function, and enhance their quality of life. We present the case of a 55-year-old female patient with bilateral KOA, who presented to Department of Regimenal therapies, National Institute of Unani Medicine, Bengaluru. The patient had taken NSAIDs and other measures intermittently for pain management from last 3 years. The symptoms have worsened from last 2 months despite taking medicines. The patient was assessed and examined clinically prior to intervention. The patient underwent treatment for 30 days with integrative therapy comprising of pharmacotherapy coupled with regimenal therapy. Prior and post intervention, the patient was assessed using multiple objective parameters. The patient reported amelioration of symptoms, which was also reflected by assessment parameters post intervention. The study found that integrative approach can be effective treatment for KOA. [ABSTRACT FROM AUTHOR]

Adiponectin, an adipokine, regulates metabolic processes, including glucose flux, lipid breakdown, and insulin response, by activating adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). We have previously shown that globular adiponectin (gAd), an endogenous form of adiponectin, has osteoanabolic and anti-catabolic effects in rodent models of postmenopausal osteopenia. Moreover, we reported the identification of a 13-mer peptide (ADP-1) from the collagen domain of adiponectin, which exhibited significant adiponectin-mimetic properties. Since the clinical development of gAd is constrained by its large size, here, we investigated the osteogenic property of ADP-1. ADP-1 induced osteoblast differentiation more potently than gAd. ADP-1 elicited osteoblast differentiation through two downstream pathways that involved the participation of adiponectin receptors. Firstly, it enhanced mitochondrial biogenesis and OxPhos, leading to osteoblast differentiation. Secondly, it activated the Akt-glycogen synthase kinase 3β-Wnt pathway, thereby increasing osteoblast differentiation. Additionally, ADP-1 suppressed the production of receptor–activator of nuclear kappa B ligand from osteoblasts, enabling it to act as a dual-action molecule (suppressing osteoclast function besides promoting osteoblast function). In osteopenic ovariectomized rats, ADP-1 increased bone mass and strength and improved trabecular integrity by stimulating bone formation and inhibiting bone resorption. Furthermore, by increasing ATP-producing intermediates within the tricarboxylic acid cycle in bones, ADP-1 likely fueled osteoblast function. Given its dual-action mechanism and high potency, ADP-1 offers a unique opportunity to address the unmet clinical need to reset the aberrant bone remodeling in osteoporosis to normalcy, potentially offering a disease-modifying impact. [ABSTRACT FROM AUTHOR]

Context Hypoparathyroidism is a rare disorder characterized by a deficiency in PTH resulting in hypocalcemia, hyperphosphatemia, and hypercalciuria. Eneboparatide is an investigational peptide agonist of the PTH1 receptor for the treatment of chronic hypoparathyroidism (HP). Objective To evaluate the efficacy, safety, and tolerability of eneboparatide in HP patients. Design Open-label, phase 2 study. Participants Twenty-eight patients (21 women, 7 men), mean age (range): 58 years (28-72), with HP were enrolled into 2 consecutive cohorts (C1, n = 12 and C2, n = 16). Intervention Following an optimization period, daily subcutaneous injections of eneboparatide were administered for 3 months at a 20 µg/day (C1) or 10 µg/day (C2) starting dose. Conventional therapy was progressively removed, and eneboparatide could be titrated up to 60 µg (C1) or 80 µg (C2). Main outcomes Proportion of patients achieving independence from conventional therapy, albumin-adjusted serum calcium (ADsCa), 24-h urine calcium (uCa), serum bone turnover markers (serum carboxy-terminal telopeptide of type I collagen and procollagen 1 intact N-terminal propeptide), bone mineral density (BMD), and adverse events (AEs). Results After 3 months, ≥ 88% of patients achieved independence from conventional therapy while mean ADsCa was maintained within target range (7.8-9 mg/dL). Eneboparatide induced a rapid and sustained reduction of mean 24-hour uCa, even among patients with hypercalciuria. Bone turnover markers slightly increased, and BMD remained unchanged, consistent with progressive resumption of physiologic bone turnover. Eneboparatide was well tolerated with no serious AEs. Conclusion Eneboparatide allowed independence from conventional therapy and maintenance of serum calcium within a target range while normalizing uCa excretion and producing a balanced resumption of bone turnover. [ABSTRACT FROM AUTHOR]

Abstract Background The gut microbiota is a key regulator of bone metabolism. Investigating the relationship between the gut microbiota and bone remodeling has revealed new avenues for the treatment of bone-related disorders. Despite significant progress in understanding gut microbiota-bone interactions in mammals, research on avian species remains limited. Birds have unique bone anatomy and physiology to support egg-laying. However, whether and how the gut microbiota affects bone physiology in birds is still unknown. In this study, we utilized laying hens as a research model to analyze bone development patterns, elucidate the relationships between bone and the gut microbiota, and mine probiotics with osteomodulatory effects. Results Aging led to a continuous increase in bone mineral density in the femur of laying hens. The continuous deposition of medullary bone in the bone marrow cavity of aged laying hens led to significant trabecular bone loss and weakened bone metabolism. The cecal microbial composition significantly shifted before and after sexual maturity, with some genera within the class Clostridia potentially linked to postnatal bone development in laying hens. Four bacterial strains associated with bone development, namely Blautia coccoides CML164, Fournierella sp002159185 CML151, Anaerostipes caccae CML199 (ANA), and Romboutsia lituseburensis CML137, were identified and assessed in chicks with low bacterial loads and chicken primary osteoblasts. Among these, ANA demonstrated the most significant promotion of bone formation both in vivo and in vitro, primarily attributed to butyrate in its fermentation products. A long-term feeding experiment of up to 72 weeks confirmed that ANA enhanced bone development during sexual maturity by improving the immune microenvironment of the bone marrow in laying hens. Dietary supplementation of ANA for 50 weeks prevented excessive medullary bone deposition and mitigated aging-induced trabecular bone loss. Conclusions These findings highlight the beneficial effects of ANA on bone physiology, offering new perspectives for microbial-based interventions for bone-related disorders in both poultry and possibly extending to human health. Video Abstract Graphical Abstract

Abstract Orthodontic relapse (OR) occurs at a rate of over 70%. Retention is the current attempt at prevention, but it requires a considerable amount of time and cannot fully block OR. It’s imperative to find a safe and effective method for managing post-orthodontic tooth stability. Periodontal bone remodeling is one crucial biological foundation of OR. Mesenchymal stem cell-derived exosomes (MSC-Exo) show promise in relapse management by regulating periodontal bone remodeling. MSC-Exo can prevent relapse by regulating periodontal ligament function, osteoclast activity, osteoblast differentiation, macrophage polarization, and periodontal microcirculation. In recent years, exosome-loaded hydrogels, which achieve controlled exosome release, have demonstrated efficacy in promoting bone regeneration and remodeling, offering promising prospects for OR management. This review aims to highlight the use of MSC-Exo-based therapy for preventing OR, offering new insights for future research focused on improving tooth stability and enhancing orthodontic anchorage.

Lysophosphatidic acid (LPA), a simple bioactive lysophospholipid widely dispersed in human body, has been reported to regulate the proliferation, chemotaxis and differentiation of multiple cells and further participate in various developmental and pathophysiological processes through at least six specific G protein-coupled receptors (GPCRs), LPA1-LPA6. Recently, the possibility of targeting LPA or LPA receptors in bone remodeling has been heatedly discussed. On the one hand, LPA modulate the activities of bone-related cells directly. On the other hand, LPA might be the potential regulator that links the nervous-vascular-immune-skeletal systems, which could provide a good microenvironment for bone remodeling and further promote bone regeneration. Thus, this review summarizes recent studies on the effects and application prospect of LPA on bone remodeling.

Abstract Erythropoietin (EPO), expressed in red blood progenitor cells, primarily regulates erythropoiesis by binding to its receptor. Besides anemia, recent studies have identified new therapeutic indications for EPO that are not connected to red blood cell formation. Elevated EPO levels harm bone homeostasis in adult organisms and are associated with increased osteoclast; however, the underlying molecular mechanisms remain unclear. This study demonstrated that EPO enhanced osteoclast differentiation and bone resorption in vitro. We showed that EPO promoted osteoclast formation by up-regulating PPARγ expression through activating the Jak2/ERK signaling pathway. Consistently, PPARγ antagonists rescued the hyperactivation of osteoclasts due to EPO, while PPARγ agonists reversed the EMP9-mediated decrease in osteoclast differentiation. Further, exposing female mice to EPO for two months led to a decrease in bone mass and increased osteoclast numbers. The present results suggested that EPO promotes osteoclastogenesis by regulating the Jak2/ERK/ PPARγ signaling pathway. From a clinical perspective, the risk of compromised bone health should be considered when using EPO to treat anemia in post-operative patients with intertrochanteric fractures of the femur, as it could significantly impact the patient’s recovery and quality of life.

This study was aimed to investigate the effects of dietary calcitriol or quercetin supplementation on eggshell and bone quality of laying hens. In trial 1, 72 Hy-Line Brown layers (80-week-old) with weak-shelled strength (25 to 30 N) were assigned into 4 dietary treatments with 6 replicates of 3 birds and fed a basal diet (4% calcium level) or basal diets supplemented with 0.5% calcium, 5 μg/kg calcitriol or 500 mg/kg quercetin for 4 weeks. In trial 2, 360 Hy-Line Brown layers (60-week-old) were divided into 3 groups with 8 replicates of 15 birds: control group (basal diet), calcitriol group (basal diet + 5 μg/kg calcitriol), and quercetin group (basal diet + 500 mg/kg quercetin). This trial lasted for 12 weeks. The results showed that dietary calcitriol or quercetin improved eggshell quality in both trials (P

Purpose: To analyze the effects of age on the sinus graft remodeling of transalveolar sinus floor elevation (SFE) with simultaneous placement of dental implants. Materials and Methods: A retrospective study design was adopted. A total of 222 sites in 216 patients who underwent transalveolar SFE with immediate implant placement were included. The clinical and radiographic data were collected at preoperative, postoperative, and postloading time points. Age was divided into three groups: < 30 years, 30 to 50 years, and > 50 years. The ratio of sinus graft resorption (Ratio) was used to evaluate the outcomes of the surgery and loading. ANOVA was applied to explore the correlation of total elevation height (TEH) with implant loading. The Ridge regression model was used to explore the relationship between Ratio and age and other possible factors. Results: A total of 222 implants in 216 patients were included for implant-based analysis. The TEH averaged 6.983 ± 2.251 mm on the day after surgery (T1), and sinus graft resorption was found during the healing period and after implant loading (P < .01). Age was found to be a reliable correlation with the Ratio (P < .01). A significantly decreased bone formation efficiency was found with aging. Conclusion: According to the results of this retrospective chart review, age was the main factor affecting the outcomes when applying transalveolar SFE with simultaneous implant placement. This finding could be a guide for clinical treatment. [ABSTRACT FROM AUTHOR]

The impact of orthopedic scaffolds on bone defect healing, particularly the late-stage bone remodeling process, is pivotal for the therapeutic outcome. This study applies fadditively manufactured scaffolds composed of hydroxyapatite-doped poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (HA-PELGA) with varying properties to treat rat calvarial defects, elucidating their significant role in bone remodeling by modulating physiological responses. We engineered two scaffolds with different polylactic acid (PLA) to polyglycolic acid (PGA) ratio (9/1 and 18/1) to vary in hydrophobicity, degradation rate, mechanical properties, and structural stability. These variations influenced physiological responses, including osteogenesis, angiogenesis, and immune reactions, thereby guiding bone remodeling. Our findings show that the HA-PELGA(18/1) scaffold, with a slower degradation rate, supported bulk bone formation due to a stable microenvironment. Conversely, the HA-PELGA(9/1) scaffold, with a faster degradation rate and more active interfaces, facilitated the formation of a thin bone layer and higher bone infiltration. This study demonstrates these degradable scaffolds help to promote bone healing and reveals how scaffold properties influence the bone remodeling process, offering a potential strategy to optimize scaffold design aiming at late-stage bone defect healing.

Introduction: Orthodontic tooth movement (OTM) involves complex interactions between mechanical forces and periodontal tissue adaptation, mainly mediated by periodontal ligament cells, including periodontal ligament stem cells (PDLSCs), osteoblasts, and osteoclasts. Dopamine (DA), a neurotransmitter known for its critical role in bone metabolism, is investigated in this study for its potential to enhance osteogenic differentiation in PDLSCs, which are pivotal in OTM. This study examined the potential of DA to facilitate OTM by binding to DA receptors (D1R and D2R) and activating the ERK1/2 signaling pathway. We propose that DA's interaction with these receptors on PDLSCs could enhance osteogenic differentiation, thereby accelerating bone remodeling and reducing the duration of orthodontic treatments, which offering a novel approach to improve clinical outcomes in orthodontic care. Methods: This study utilized a rat OTM model, micro-CT, histological analyses, and in vitro assays to investigate dopamine's effect on osteogenesis. PDLSCs were cultured and treated with DA, and cytotoxicity, osteogenic differentiation, gene and protein expression assessed. Results: Dopamine administration significantly increased trabecular bone density and osteogenic marker expression in an OTM rat model. In vitro, DA at 10 nM optimally promoted human PDLSCs osteogenesis without affecting proliferation. Blocking DA receptors or inhibiting the ERK1/2 pathway attenuated these effects, underscoring the importance of dopaminergic signaling in tension-induced osteogenesis during OTM. Conclusion: Taken together, our study reveals that local dopamine administration at a concentration of 10 nM not only enhances tension-induced osteogenesis in vivo but also significantly promotes osteogenic differentiation of PDLSCs in vitro through D1 and D2 receptor-mediated ERK1/2 signaling pathway activation.

BACKGROUND: In recent years, numerous studies have found that long non-coding RNA is involved in the occurrence and development of osteoporosis. p38MAPK signaling pathway is involved in the differentiation of bone marrow mesenchymal stem cells, osteoblasts and osteoclasts, and participates in the development of osteoporosis. LncRNA can directly or indirectly participate in the occurrence and development of osteoporosis by affecting the p38MAPK signaling pathway. OBJECTIVE: To review the effect of long non-coding RNA directly or indirectly on the progression of osteoporosis through the p38MAPK signaling pathway, and to provide a new idea for long non-coding RNA in the prevention and treatment of osteoporosis. METHODS: PubMed, CNKI, and Wanfang databases were searched with “long non-coding RNA, osteoporosis, mesenchymal stem cells, osteoblasts, osteoclasts, p38 signaling pathway” as the Chinese and English search terms. Old, repeated and low-credibility views were excluded. The retrieved literature was summarized, summed up, and analyzed. Seventy-six representative articles were selected. RESULTS AND CONCLUSION: (1) Long non-coding RNA participates in the prevention and treatment of osteoporosis through a variety of ways, including promoting the osteogenic differentiation of bone marrow mesenchymal stem cells, promoting the differentiation and secretion activity of osteoblasts, inhibiting the proliferation and bone resorption of osteoclasts, and regulating the activation or inhibition of osteoblast-related cellular pathways. Activation of p38MAPK signaling pathway can delay the progression of osteoporosis, and inhibition of p38MAPK signaling pathway can inhibit the absorption of osteoclasts, thereby affecting the occurrence and development of osteoporosis. (2) The overexpression or low expression of the corresponding long non-coding RNA can affect the proliferation or differentiation of osteoblasts and osteoclasts through the p38MAPK signaling pathway, regulate the process of bone remodeling, and then affect the occurrence and development of osteoporosis. A large number of basic research results show that long non-coding RNA and p38MAPK signaling pathway may be potential application and clinical translation value in the treatment of osteoporosis. Moreover, the corresponding long non-coding RNA overexpression or low expression lentivirus, transfection plasmid, and the corresponding p38MAPK signaling pathway inhibitor have been confirmed to have targeted regulatory effects in vitro cell experiments and animal models. (3) Therefore, targeting long non-coding RNA and p38MAPK signaling pathways to regulate the differentiation and function of bone marrow mesenchymal stem cells or inhibiting the proliferation and differentiation of osteoclasts may provide an innovative therapeutic strategy to delay the progression of osteoporosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Osteoarthritis is one of the most common senile chronic degenerative diseases in China. Due to its complex pathogenesis and cellular molecular communication pathways, there is currently no effective method to slow down the progression of osteoarthritis. Studies have found that transforming growth factor-β is one of the key factors in the maintenance and regulation of joint stability and plays a significant role in the formation of early joints, as well as the development of bone and cartilage, and the remodeling of joints at various stages. OBJECTIVE: To review the regulatory role of the transforming growth factor-β subfamily in the occurrence and development of osteoarthritis, both domestically and internationally in recent years, to analyze the impacts it has at different stages of osteoarthritis, and to explore the potential application prospects of transforming growth factor-β in the clinical treatment of osteoarthritis, with a view to informing clinical treatment protocols.. METHODS: The relevant articles were searched by computer from CNKI Database and PubMed Database. The search terms were “osteoarthritis, transforming growth factor, signaling pathway, bone remodeling, cartilage degeneration, angiogenesis, treatment” in Chinese and English, respectively. Finally, 57 articles were included for review. RESULTS AND CONCLUSION: The pathogenesis of osteoarthritis remains a subject of ongoing exploration with no unified consensus. Numerous studies highlight the close correlation between osteoarthritis and cytokines, focusing on the transforming growth factor-β superfamily as a pivotal mechanism and therapeutic breakthrough. Transforming growth factor-β plays a crucial role in early joint cartilage formation and maintenance, promoting cartilage repair. However, post-joint formation, its protective effect weakens, leading to potential destructive consequences. This dual regulatory role is a current clinical treatment focus, necessitating further research to delineate its application scope for standardized protocols. Highly active transforming growth factor-β participates in the regulation of bone cells, osteoblasts, and osteoclasts under mechanical stress, and intervenes in the subsequent remodeling of bone microstructure. Specific inhibitors present potential targeted therapeutics, yet their safety and efficacy in clinical settings require refinement. Vascular proliferation may serve as a potential disruptive pathway in transforming growth factor-β-mediated cartilage degeneration and subchondral bone remodeling. Abnormal communication pathways can further disrupt the homeostasis of the microenvironment of osteochondral units, thereby accelerating key pathological progressions of osteoarthritis. Research on transforming growth factor-β in osteoarthritic contexts is comprehensive, holding broad clinical application prospects. Drugs related to transforming growth factor-β are in clinical trial phases, but addressing potential impacts on other tissues and precise control of targeted delivery are critical concerns. As research advances, there is optimism for innovative breakthroughs in slowing the progression of osteoarthritis in the future. [ABSTRACT FROM AUTHOR]

BACKGROUND: The application of orthodontic force triggers autophagy in the periodontal tissue via diverse signaling pathways, augmenting or attenuating the activity of relevant cell types such as periodontal ligament cells, osteocytes, osteoclasts, and osteoblasts, thus facilitating the process of periodontal remodeling. OBJECTIVE: To review the research progress in orthodontic force mediated autophagy in periodontal tissue and its impact on orthodontic tooth movement. METHODS: The PubMed, Web of Science, China Biology Medicine disc and CNKI were searched for literature published from 2010 to 2023 to summarize the progress in orthodontics-related autophagy. And 76 papers were finally included in the analysis and discussion. RESULTS AND CONCLUSION: Orthodontic force can trigger a series of biochemical signal changes through periodontal mechanical receptors and aseptic inflammation they cause, leading to autophagy in periodontal tissue. Subsequently, autophagy generates corresponding feedback through cascaded amplified signaling pathways such as Phosphoinositide 3-kinase/protein kinase B, Hippo, and mitogen-activated protein kinase pathways, promoting periodontal tissue remodeling and ultimately achieving tooth movement and stability. Orthodontic force-induced autophagy can differentially regulate bone resorption on the tooth pressure side and bone formation on the tension side. Related targets have good prospects in the clinical application of orthodontic treatment. Orthodontics and autophagy have complex mechanisms. However, existing research has only focused on exploring the role of autophagy in orthodontic tooth movement. Further exploration is needed to investigate the mutual regulatory effects between autophagy and orthodontic tooth movement, as well as the interactions between upstream mechanical receptors and signaling pathways involved in related pathways. [ABSTRACT FROM AUTHOR]

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Large acetabular bone defects are challenging in hip revision surgery. Clinical assessment is crucial to evaluate modern technologies in surgical reconstruction. We aimed to better understand the bone remodeling that occurs following acetabular reconstruction. Our objectives were: (1) To characterize changes in the shape of the pelvis by studying sequential computed tomography (CT) scans collected immediately and 1‐year postoperatively and (2) to identify which part of the pelvis is most susceptible to remodeling. We used the CT scans taken at two timepoints, of 24 patients with acetabular bone defects classified as Paprosky IIIB, treated with three‐dimensional (3D)‐printed custom‐made acetabular implants. Segmented 3D models of the bony pelvis were co‐registered using three different techniques. A global co‐registration of the full pelvis was conducted, followed by the co‐registration of the innominate bone and then ilium only, on the ipsilateral reconstructed side. The relative movements of the ilium, ischium, and pubis were analyzed from visual inspection and using co‐registration metrics (root mean square error and intersection over union). No bone remodeling was found in 14/24 patients (58%). The co‐registration of the innominate bone indicated bone remodeling in five cases (21%), while the remaining five cases (21%) presented remodeling in the global co‐registration but not the innominate bone co‐registration, suggestive of changes occurring at the sacroiliac joint. Changes in the pelvic shape were greatest at the pubis and ischium. Bone remodeling may occur in complex cases of Paprosky type IIIB defects, after acetabular reconstruction (occurrence of 21%, 5/24 cases). Surgeons and engineers should consider this when monitoring implant migration. [ABSTRACT FROM AUTHOR]

The current study aims to prepare and compare three injectable hydrogels consisting of chitosan, hyaluronic acid, and hydroxyapatite in different combinations using two solvents and homoginizer that can be employed in bone tissue engineering (BTE) for remodelling and healing bones. The hydrogel structures were well characterized by FT-IR, XRD and SEM analyses. Surface study, porosity, percolation capacity, bone cell adhesion and proliferation, and swelling properties were tested and was found that these hydrogels are better candidates for BTE. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) analysis showed better compatibility with mononuclear cells derived from human peripherals. Our findings suggest that these hydrogels can be efficiently used as injectable hydrogels in BTE applications. [ABSTRACT FROM AUTHOR]

Objective: Patients with type IIA craniofacial microsomia (CFM) may benefit from mandibular distraction osteogenesis (MDO) treatment during childhood; however, remodelling of the mandible during the consolidation phase, which may affect the short‐term outcomes of MDO, has not yet been quantitatively analysed using computed tomography. Therefore, we aimed to investigate bone remodelling of the mandible in children with type IIA CFM treated with MDO before distractor removal and the factors that influence ramus vertical elongation efficiency. Materials and Methods: Twenty‐three children with unilateral CFM were studied between 2020 and 2024. Longitudinal computed tomography data (preoperative, end of active phase and at pre‐distractor removal) were analysed. Condyle positions and the mandibular cant were analysed using a paired‐sample t test. The relapse rates of vertical lengthening and mandibular cant were calculated. The correlation between distraction efficiency and preoperative craniofacial morphology was analysed. Results: The condyle on the affected side moved upwards and backwards by 28.84 ± 4.08 and 2.85 ± 4.33 mm, respectively during the active phase but lost 7.66 ± 2.64 mm of vertical extension during the consolidation phase. The relapse rates for vertical extension of the condyle and occlusal plane were 27% and 35%, respectively. The ratio of mandibular ramus height was positively related to EV. Conclusions: In children with CFM, attention should be paid to vertical elongation instability and relapse of mandibular inclination during consolidation. Severe mandibular ramus hypoplasia is a preoperative risk factor for vertical skeletal relapse during consolidation. Further efforts are required to reduce the stress that leads to relapse. [ABSTRACT FROM AUTHOR]

Current evidence suggests that proper implant transmucosal contouring can significantly impact supracrestal soft tissue development and crestal bone response both in early and late stages of treatment. The macrodesign and composition of the anatomical healing abutment or temporary prosthesis used during transmucosal contouring are crucial elements for establishing biologic and prosthetic conditions that minimize early bone remodeling, improve esthetic outcomes, and reduce the possibility for future peri-implant inflammation. This article presents clinical directions on the design and fabrication processes of anatomical healing abutments or temporary prostheses for single implant sites under the interpretation of currently available scientific data. [ABSTRACT FROM AUTHOR]

This study evaluated how implant design features influence osseointegration. Two implant macrogeometries and surface treatments were evaluated: (1) progressive buttress threads with an SLActive surface (SLActive/BL), and (2) inner and outer trapezoidal threads with a nanohydroxyapatite coating over a dual acid-etched surface (Nano/U). Implants were placed in the right ilium of 12 sheep, and histologic and -metric analyses were conducted after 12 weeks. Percentages of bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) within the threads were quantified. Histologically, the SLActive/BL group showed greater and more intimate BIC than the Nano/U group. In contrast, Nano/U group depicted woven bone formation within the healing chambers, between the osteotomy wall and implant threads, and bone remodeling was evident at the outer thread tip. Significantly higher BAFO was seen in the Nano/U group than the SLActive/BL group at 12 weeks (P < .042). Different implant design features influenced the osseointegration pathway, supporting further investigations to describe the differences and clinical performance. [ABSTRACT FROM AUTHOR]