Resorption Markers Research Articles

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice.

Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender. 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0-2 year change in Z-scores of +0.1, -0.4, and -1.2, respectively. This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.

Increased Bone Turnover and Decreased BCMA Levels in Patients with Response to Anti-BCMA CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma

Introduction For most patients (pts), multiple myeloma (MM) remains an incurable disease. Osteolytic lesions (OL) are present in 80% of pts at diagnosis and skeletal-related events are the most common cause for symptomatic relapse. Hence, myeloma bone disease (MBD) is a major cause of morbidity and mortality especially among pts with relapsed/refractory MM (RRMM). B cell maturation antigen (BCMA) targeted chimeric antigen receptor (CAR) T cells have revolutionized treatment of patients with RRMM. While remission rates are high and pts experience long-standing treatment free intervals after CAR T cell treatment, little is known about its effects on MBD and bone turnover. The latter can be determined in plasma by measuring markers of bone formation and resorption. We aimed to analyze the longitudinal development of bone turnover during and after anti-BCMA CAR T cell treatment in RRMM pts. Methods We analyzed 28 consecutive pts with RRMM who underwent treatment with either Idecabtagene-Vicleucel (n=27) or Ciltacabtagen-Autoleucel (n=1) at our center between December 2021 and February 2023. Median age at infusion was 63 (range 39-75) years. 57% of pts were male. All pts were triple-class exposed, 21% had penta-class refractory disease. Status prior to CAR T cell infusion was complete remission (CR, 11%), partial remission (PR, 21%), very good PR (14%), stable disease (4%), or progressive disease (PD, 50%). The impact of CAR T cell treatment on bone turnover was assessed by collecting plasma samples on the day of T cell apheresis, as well as days (d) 30 and 100 after CAR T cell infusion. Samples were analyzed by ELISA to evaluate plasma levels of bone formation marker Osteocalcin (OCN), bone resorption markers Tartrate-resistant acid phosphatase 5b (TRAcP5b) and fibroblast growth factor 23 (FGF23) as well as BCMA as a marker for the targeted myeloma cells. Median levels were compared between subgroups by Wilcoxon tests. Remission status after CAR T cell therapy was first evaluated at d 30 according to International Myeloma Working Group consensus criteria. Median follow-up was 6 months. Results Of the 28 pts treated with anti-BCMA CAR T cells, 64% achieved at least a PR (responders), while 36% had PD shortly (30 d) after. Within 14 d after infusion, 82% developed a cytokine release syndrome (CRS, °I or II), in 30% of which Tocilizumab was applied. Only 1 pt developed immune effector cell-associated neurotoxicity syndrome. In responders, BCMA levels in plasma decreased significantly between apheresis and d 30 ( P<.01) and between apheresis and d 100 ( P<.01), while pts with PD showed no significant change in BCMA levels at the same timepoints ( P=.6 and P=.8). Furthermore, BCMA levels were significantly higher in pts with PD at d 30 ( P<.01) and d 100 ( P=.02), compared to responders (Figure 1). Regarding bone resorption markers, TRAcP5b levels were significantly increased in responders ( P=.01) but not pts with PD ( P=.56) on d 30 after apheresis. Furthermore, we determined a significant increase of intact FGF23 between apheresis and d 30 ( P<.01) and a subsequent significant decrease of intact FGF23 ( P=.02) between d 30 and d 100 in responders. Since FGF23 and interleukin-6 (IL-6) are physiologically dependent, the observed FGF23 dynamics are likely to be an effect of increasing IL-6 in the context of CRS. Aptly, pts who received Tocilizumab because of full-blown CRS had higher intact FGF23 levels at d 30 ( P=.02) compared to pts without Tocilizumab treatment. The bone formation marker OCN showed a significant increase in responders between apheresis and d 100 ( P=.01), as well as between d30 and d100 ( P=.02), while there were no significant changes in OCN levels over the time in pts with PD (Figure 2). Conclusion Pts responding to treatment with anti-BCMA CAR T cells, showed an increased bone turnover shortly after infusion. The increase of bone resorption marker levels appeared to be a short-term trend and could possibly be related to inflammation and high interleukin levels during the first days after infusion. However, we also saw a steady increase of bone formation marker OCN, which remained significant till d 100 in responders. Our data implies, that response to anti-BCMA CAR T cells is accompanied by increasing bone formation. Further analyses are needed to evaluate, whether this treatment can have positive long-term effects on MBD.

Association of bone turnover markers and cognitive function in Chinese chronic schizophrenia patients with or without vitamin D insufficiency

BackgroundIncreasing evidence shows that bone turnover markers (BTMs) and vitamin D can affect human cognitive function. However, there are few studies that have investigated the association between BTMs and cognitive function in chronic schizophrenia patients. The aim of this study was to investigate the relationship between BTMs and cognitive function in chronic schizophrenia patients with or without vitamin D insufficiency (VDI).MethodsIn all, 118 chronic schizophrenia patients were enrolled in this cross-sectional study. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to evaluate the cognitive function of the subjects. Blood analysis included bone turnover markers, vitamin D levels, and glycolipid levels.ResultsRelative to 72 vitamin D-sufficient (VDS) patients, 46 VDI patients had higher bone resorption markers levels and lower bone formation markers levels. Regression analysis showed that, in the total sample, CTX and language function exhibited independent positive correlation (p = 0.027, R2 change = 0.042), and in the VDS group, procollagen type I N-terminal propeptide (PINP) was independently negatively correlated with language function (p = 0.031, R2 change = 0.065), while the positive correlation between osteopontin (OPN) and delayed memory remained in the VDI group (p = 0.036, R2 change = 0.083).ConclusionOur study showed an association between the levels of BTMs and cognitive function among chronic schizophrenia patients. This correlation may have different mechanisms of action at different vitamin D levels.

Characteristics of bone metabolism disorders in military personnel in the Arctic regions: prospective study

OBJECTIVE. To study characteristics of bone metabolism disorders in military personnel in the Arctic regions.
 MATERIALS AND METHODS. The survey was conducted and medical documentation of 189 male soldiers aged 23–42 (average age - 29,6±5,6) was studied. Depending on the duty station all the surveyed were divided into two groups: I – 107 soldiers, performing military service in the Arctic regions with at least 2 years of experience, II – 82 soldiers from the Western Military Region. Complaints, anamnesis data, objective status (including anthropometry) and medical documentation were assessed and studied in the surveyed military personnel. For estimating bone-mineral density, the method of calcaneus ultrasonography, using «GE Healthcare Achilles» densitometer was applied. The content of total calcium, inorganic phosphorus as well as the concentration of bone resorption markers – СТХ and NTX in the blood serum were used as analyzed laboratory rate of bone metabolism.
 RESULTS. The study showed that almost half of the military personnel in the Arctic regions (48,6%) had the rate of bone-mineral density below the average value for healthy men of the same age group. It was noted that prevalence of osteopenia in the Arctic is significantly higher compared to military personnel from temperate regions. When studying bone resorption markers, it was noted that the group of Arctic military personnel experienced statistically significant increase in NTX, characterizing the rate of degradation in the newly formed bone as well as the tendency towards increase in CTX, reflecting the rate of degradation relative to the old bone.
 DISCUSSION. The main link in the pathogenesis of low bone-mineral density in military personnel in the unfavorable Arctic environment is D3 vitamin metabolism disorder by lowering its formation in the skin and also it limited intake with food. High prevalence of disorder in bone-mineral density among Arctic military personnel might indicate the need for a more rigorous selection process in the Arctic regions with a mandatory in-depth survey of the bone metabolism system (determination of total calcium content, inorganic phosphorus, D3 vitamin) as well as performing according to osteodensitometry. It is advisable to conduct an annual survey of the Arctic military personnel at the duty station, involving a visiting military-medical commission with a therapist or rheumatologist as its member.

Serum levels of bone turnover markers including calculation of Z-scores: Data from a Dutch healthy reference cohort

IntroductionBone turnover markers (BTM) are biochemical compounds reflecting different stages of bone metabolism. Their levels change with age and differ between males and females. This makes clinical interpretation and comparison more difficult. Therefore, our aim was to establish BTM reference values which can be used to calculate Z-scores for use in daily clinical practice. MethodsSerum markers of collagen resorption, bone formation/regulation, collagen formation and bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured in non-fasting volunteers without bone-related abnormalities. Raw data was plotted and gender-specific age cohorts were established with their respective means and standard deviations (SD). Z-scores can be calculated using these reference values to correct for the influence of age and gender on BTM. ResultsIn total, 856 individuals were included of which 486 (57 %) were female. Individuals were aged between 7 and 70 years. Highest serum levels of BTM were found in childhood and puberty. Peak levels are higher in boys than girls and prevail at later ages. In adults, BTM levels decrease before reaching stable nadir levels. In adults, 10-year reference cohorts with means and SD were provided to calculate Z-scores. ConclusionWith our data, Z-scores of sCTX, OC, PINP and BALP can be calculated using reference categories (for age and gender) of Caucasian healthy volunteers. Clinicians can use BTM Z-scores to determine whether there are changes in bone turnover physiology beyond those expected during aging. BTM Z-scores facilitate harmonization of data interpretation in daily clinical practice and research.

Role of immunological and biochemical markers in bone turnover in type I diabetic patients in Karbala province, Iraq

Introduction & Aim: Long-term diabetes mellitus (DM) is known to have a deleterious impact on bone health, resulting in change in bone mineral density, bone turnover, and bone quality, all of which increase the risk of fractures. The aim of. this study was to link immunological and pro-inflammatory cytokine (I.L-6, I.L-1, and TNF-alpha) markers in patients.with type 1 diabetes to Their connection to bones formation (sPINP) and bone resorption parameters (sCTX). Materials & Methods: This study included 80 patients suffering from T1DM in the age range of 20-45 years. The patients were assayed for their biochemical (Vitamin D and HbA1c), Immunological (IL-6, IL-1 and TNF-alpha) parameters, as well as bone formation and resorption markers. Results: HbA1c values were observed to be 7.5 in 85% of individuals, while vitamin D levels were 16 ng/mL. Correlation in patients with HbA1c 7.5. The results of a linear regression between I.L-6 and sCTX showed that there was an increase in sCTX for each unit of IL-6. Conclusion: In patients with HbA1c levels 7.5, there is an association between IL-6, TNFalpha, and the bone resorption. TNF-alpha and IL-6 have been linked to metabolic control loss.

Impact of Dietary Protein on Osteoporosis Development.

Osteoporosis is a frequent yet unsolved health problem among older people. The influence of dietary protein still raises many questions regarding its quality and quantity in the context of bone health. The aim of this manuscript is to review the latest evidence on plant and animal protein influences on bone health in various groups of patients. The review is based on original studies, meta-analyses, randomized controlled trials, and prospective cohort studies published in PubMed and Cochrane databases during the last five years. Combining plant and animal protein with physical activity has the best effect on bones (muscle strengthening and reducing the risk of falls), while high protein intake can have adverse effects during bed rest. Despite the content of isoflavones, plant protein is not more beneficial than animal protein (dairy products) and can increase bone resorption markers. Hypoestrogenism due to menopause or eating disorders leads to low bone density and an increased risk of osteoporosis. A well-balanced diet with sufficient energy supply and protein intake (both of plant and animal origins) and adequate physical activity are crucial to ensure bone health. Dietary interventions should consider the quantity and quality of protein in patients with other comorbidities, particularly in an aging society.

Bridging the bone gap: a prospective study protocol on osteoporosis risk in Portuguese patients with spinal cord injury

Spinal Cord Injury is associated with a decrease in bone mineral density and consequently an increased risk of fragility fractures. This prospective study protocol, aims to investigate the risk factors and prevalence of osteoporosis in a Portuguese population of spinal cord injured patients. By analyzing a range of variables, including not only personal and family history, lifestyle factors, and injury severity, but also bone mineral density and biochemical markers of bone resorption, the research seeks to enhance our understanding of osteoporosis in spinal cord injury patients and improve preventive measures. The effectiveness of pharmacological interventions is greater when started soon after the injury, therefore, prompt diagnosis and treatment of osteoporosis are essential to prevent the complications associated with this condition, particularly osteoporotic fractures.

Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.

Noonan, Costello and Cardio-facio-cutaneous syndromes belong to a group of disorders named RASopathies due to their common pathogenetic origin that lies on the Ras/MAPK signaling pathway. Genetics has eased, at least in part, the distinction of these entities as they are presented with overlapping clinical features which, sometimes, become more pronounced with age. Distinctive face, cardiac and skeletal defects are among the primary abnormalities seen in these patients. Skeletal dysmorphisms range from mild to severe and may include anterior chest wall anomalies, scoliosis, kyphosis, short stature, hand anomalies, muscle weakness, osteopenia or/and osteoporosis. Patients usually have increased serum concentrations of bone resorption markers, while markers of bone formation are within normal range. The causative molecular defects encompass the members of the Ras/MAPK/ERK pathway and the adjacent cascades, important for the maintenance of normal bone homeostasis. It has been suggested that modulation of the expression of specific molecules involved in the processes of bone remodeling may affect the osteogenic fate decision, potentially, bringing out new pharmaceutical targets. Currently, the laboratory imprint of bone metabolism on the clinical picture of the affected individuals is not clear, maybe due to the rarity of these syndromes, the small number of the recruited patients and the methods used for the description of their clinical and biochemical profiles.

Hand grip strength, vitamin D status, and diets as predictors of bone health in 6–12 years old school children

BackgroundVitamin D and calcium-rich foods, exposure to sunlight, and physical activities (PA) play a pivotal role in promoting the production of sufficient vitamin D and improving grip strength needed for better bone health among school children.PurposeThis study aimed to determine the effects of hand grip muscle strength (HGS), vitamin D in addition to diets, and PA on bone health status among 6–12 years old schoolchildren.MethodsThis study was based on a cross-sectional observational design, which was descriptive in nature. A diverse sample of 560 elementary school children aged 6–12 years old were invited to participate in this descriptive cross-sectional study. The Dual-Energy X-Ray Absorptiometry (DXA), QUS technique, and ACTi graph GT1M accelerometer were used respectively as a valid tools to identify BMD, BMC, and other parameters of bone health like c-BUA values and bone stiffness (SI), and physical activity (PA) of all individuals participated in this study. In addition, a hydraulic dynamometer was used to measure hand grip strength among the participants. Moreover, an immunoassay technique was used to measure the serum levels of vitamin 25(OH)D level, and bone metabolism markers; NTX, DPD, Ca, and sBAP in all participants. Bone loss (osteoporosis) was cross-sectionally predicted in 19.64% of the total population, most of whom were girls (14.3% vs. 5.4% for boys; P = 0.01). Compared to boys, the incidence of osteoporosis was higher and significantly correlated in girls with lower HGS, deficient vitamin D, inadequate vitamin D and Ca intake, greater adiposity, poor PA, and lower sun exposure. Also, in girls, lower vitamin 25(OH)D levels, and poor HGS were shown to be significantly associated with lower values of BMD, BMC, SI, and higher values of bone resorption markers; NTX, DPD, and sBAP and lower serum Ca than do in boys. The findings suggested that deficient vitamin D, lower HGS, adiposity, PA, and sun exposure as related risk factors to the pravelence of bone loss among school children, particularly in girls. In addition, these parameters might be considered diagnostic non-invasive predictors of bone health for clinical use in epidemiological contexts; however, more studies are required.

Correlation between bone mineral density and bone metabolic markers in postmenopausal women with osteoporotic fractures at different C-terminal telopeptide of type 1 collagen levels: a retrospective analysis study.

This study aimed to analyze the correlation between bone mineral density (BMD) and bone resorption markers in postmenopausal women with osteoporosis fractures and identify risk factors for second fractures. This retrospective analysis of 1,239 older women with fractures with a median age of 70 years who attended Shanghai General Hospital from January 2007 to December 2016, included a first fracture group (1,008 cases) and a second fractures group (231 cases). The risk factors for fractures were analyzed by comparing these groups on clinical characteristics, BMD, and bone metabolism markers stratified by quartiles of serum C-terminal telopeptide of type 1 collagen (CTX). Binary logistic regression analysis was used to identify risk factors for second fractures. In the whole sample, BMD was negatively correlated with age and serum osteocalcin and positively correlated with body mass index (BMI). In women with first fractures, those in the highest quartile of serum CTX had the lowest spine and hip BMD. Second fractures were significantly associated with BMI, lower spine and hip BMD, and higher serum osteocalcin but not CTX. Binary logistic regression analysis showed that high BMI (odds ratio [OR], 1.08 [95% CI, 1.03-1.14]; P = 0.001), low lumbar BMD (OR, 0.24 [95% CI, 0.07-0.82]; P = 0.023), low total hip BMD (OR, 0.05 [95% CI, 0.00-0.88]; P = 0.041), and lack of antiosteoporosis treatment (OR, 2.71 [95% CI, 2.71-4.08]; P < 0.001) were independent risk factors for second fractures. In older women with fractures, BMD was significantly lower in women with second fractures than in those with first fractures. Higher levels of serum CTX and osteocalcin, which indicates increased bone resorption, were negatively correlated with BMD. In women with a first fracture, serum CTX higher than 605 pg/mL was negatively correlated with BMD, whereas no correlation was found between different CTX and BMD in women with second fractures. High BMI and low BMD as well as not receiving antiosteoporosis treatment were independent risk factors for second fractures.

Influence of sport type and gender on bone turnover markers in young athletes

BackgroundExercise is beneficial to bone health. However, little is known about the interaction effect of gender and sport type on bone turnover in young athletes. This study aimed to examine the influence of gender and sports categories (high, medium, and low impact) on bone turnover: reabsorption markers–osteocalcin, calcium, inorganic phosphate (IP), alkaline phosphatase (ALP), and resorption marker–cross-linked N-telopeptides of type 1 collagen (NTx) among a university’s undergraduate athletes.MethodsThe study was an ex-post facto design involving forty-seven purposively recruited gender- and sport-type-matched undergraduate athletes whose demographic characteristics and BMI were obtained. Participants’ 5 mL antecubital blood samples were collected and analysed for serum levels of osteocalcin, calcium, IP, ALP, and NTx using standard laboratory protocols, Bio-Tek spectrometer, and KC4 (3.3) software. Data were analysed using descriptive statistics and two-way ANOVA.ResultsThe study involved 24 females and 23 males (n = 47) aged 22.15 ± 3.35 years with an average BMI of 23.34 ± 4.66. There was no significant gender effect on the biomarkers. However, there was a significant effect of the sports category on IP (F = 4.307, p = 0.020), calcium (F = 6.807, p = 0.003), and ALP serum levels (F = 11.511, p < 0.001). Specifically, mid-impact sports participants had a higher IP than the low-impact group (mean difference [MD] = 0.81 mg/dL, p = 0.036). Low-impact had a higher calcium level than mid-impact (MD = 0.40 mg/dL, p = 0.022) and high-impact (MD = 0.49 mg/dL, p = 0.003). Conversely, low-impact had lower ALP than mid-impact (MD = − 11.13 U/L, p = 0.013) and high-impact (MD = − 17.44 IU/L, p < 0.001).ConclusionModerate to high-impact sports positively affected bone turnover in young athletes. However, gender had no significant impact.

Isolation and Characterization of an Anti-Osteoporotic Compound from Melia toosendan Fructus.

Melia toosendan fructus, traditionally employed in traditional Chinese and Korean herbal medicine, exhibits diverse biological properties encompassing anti-tumor, anti-inflammatory, and anti-viral effects. However, its influence on bone metabolism remains largely unexplored. In this study, we investigated the impact of an ethanolic extract of Melia toosendan fructus (MTE) on osteoclast differentiation and characterized its principal active constituent in osteoclast differentiation and function, as well as its effects on bone protection. Our findings demonstrate that MTE effectively inhibits the differentiation of osteoclast precursors induced by receptor activator of nuclear factor κB ligand (RANKL). Utilizing a bioassay-guided fractionation approach coupled with UHPLC-MS/MS analysis, we isolated and identified the triterpenoid compound toosendanin (TSN) as the active constituent responsible for MTE's anti-osteoclastogenic activity. TSN treatment downregulated the expression of nuclear factor of activated T cells c1, a pivotal osteoclastogenic transcription factor, along with molecules implicated in osteoclast-mediated bone resorption, including tumor necrosis factor receptor-associated factor 6, carbonic anhydrase II, integrin beta-3, and cathepsin K. Furthermore, treatment of mature osteoclasts with TSN impaired actin ring formation, acidification, and resorptive function. Consistent with our in vitro findings, TSN administration mitigated trabecular bone loss and reduced serum levels of the bone resorption marker, C-terminal cross-linked telopeptides of type I collagen, in a mouse bone loss model induced by intraperitoneal injections of RANKL. These results suggest that TSN, as the principal active constituent of MTE with inhibitory effects on osteoclastogenesis, exhibits bone-protective properties by suppressing both osteoclast differentiation and function. These findings imply the potential utility of TSN in the treatment of diseases characterized by excessive bone resorption.

Conditional knockout of PDK1 in osteoclasts suppressed osteoclastogenesis and ameliorated prostate cancer-induced osteolysis in murine model

BackgroundThe development and maintenance of normal bone tissue is maintained by balanced communication between osteoblasts and osteoclasts. The invasion of cancer cells disrupts this balance, leading to osteolysis. As the only bone resorbing cells in vivo, osteoclasts play important roles in cancer-induced osteolysis. However, the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in osteoclast resorption remains unclear.MethodsIn our study, we used a receptor activator of nuclear factor-kappa B (RANK) promoter‐driven Cre‐LoxP system to conditionally delete the PDK1 gene in osteoclasts in mice. We observed the effect of osteoclast‐specific knockout of PDK1 on prostate cancer-induced osteolysis. Bone marrow-derived macrophage cells (BMMs) were extracted and induced to differentiate osteoclasts in vitro to explore the role of PDK1 in osteoclasts.ResultsIn this study, we found that PDK1 conditional knockout (cKO) mice exhibited smaller body sizes when compared to the wild-type (WT) mice. Moreover, deletion of PDK1 in osteoclasts ameliorated osteolysis and rPDK1educed bone resorption markers in the murine model of prostate cancer-induced osteolysis. In vivo, we discovered that osteoclast‐specific knockout of suppressed RANKL-induced osteoclastogenesis, bone resorption function, and osteoclast-specific gene expression (Ctsk, TRAP, MMP-9, NFATc1). Western blot analyses of RANKL-induced signaling pathways showed that conditional knockout of PDK1 in osteoclasts inhibited the early nuclear factor κB (NF-κB) activation, which consequently suppressed the downstream induction of NFATc1.ConclusionThese findings demonstrated that PDK1 performs an important role in osteoclastogenesis and prostate cancer-induced osteolysis by modulating the PDK1/AKT/NF-κB signaling pathway.

THU428 Association Of Bone Turnover Markers Monitoring With Osteoporosis Medication Adherence In Korea: A Nationwide Cohort Study

Abstract Disclosure: S. Ahn: None. S. Park: None. M. Kwak: None. S. Kim: None. T. Kim: None. H. Kim: None. S. Hong: None. Objective: Bone turnover markers (BTMs) are non-invasive and useful biomarkers for predicting the risk of fractures and monitoring the adherence and response to medical treatment in patients with osteoporosis. However, the contribution of BTMs in the improvement of osteoporosis medication adherence has not been well studied. Therefore, we investigated the association of BTMs monitoring with medication adherence in Korean osteoporosis patients. Methods: We used data from the Korean National Health Insurance Service. Among 1,440,538 osteoporosis patients ≥50 years who started with medical treatment during 2010-2014, we selected 118,598 patients who monitored BTMs at least once during 2 years of follow up (BTM group) and 362,794 age-, sex-, and medication initiation year-matched controls who never measured BTMs (NO-BTM group). Adherence to medical treatment was defined as medication possession ratio ≥80%. Multivariable logistic regression analysis was used to determine the association of BTMs monitoring with adherence at 2 year follow up. Results: Among BTM group, 92.5% and 87.1% patients monitored bone resorption or formation markers at least once during 2 years of follow up, respectively. However, only 36.0% of patients monitored BTMs more than twice. MPRs at 2 year follow up were higher in BTM group than in NO-BTM group (41.4% vs. 26.5%, P&amp;lt;0.001). Among BTM group, MPRs were higher in patients who monitored bone resorption markers than in patients who never monitored them (41.7% vs. 36.1%, P&amp;lt;0.001) and in patients who monitored BTMs more than twice than in patients who monitored them only once (55.6% vs. 32.9%, P&amp;lt;0.001). BTMs monitoring showed positive association with MPRs at 2 year follow up (β = 3.055, SE = 0.137, P&amp;lt;0.001) after adjusting for confounders. BTMs monitoring was associated with increased OR (1.17, 95% CI 1.15-1.20, P&amp;lt;0.001) for better adherence to medical treatment at 2 year follow up after adjusting for confounders. Conclusion: In this retrospective study, monitoring of BTMs was associated with better adherence to medical treatment in Korean patients with osteoporosis. Presentation: Thursday, June 15, 2023

Changes in bone and mineral homeostasis after short-term androgen deprivation therapy with or without androgen receptor signalling inhibitor – substudy of a single-centre, double blind, randomised, placebo-controlled phase 2 trial

Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) have an increased fracture risk. Exploring biomarkers for early bone loss detection is of great interest. Pre-planned substudy of the ARNEO-trial (NCT03080116): a double blind, randomised, placebo-controlled phase 2 trial performed in high-risk PCa patients without bone metastases between March 2019 and April 2021. Patients were 1:1 randomised to treatment with gonadotropin-releasing hormone antagonist (degarelix)+androgen receptor signalling inhibitor (ARSI; apalutamide) versus degarelix+matching placebo for 12 weeks prior to prostatectomy. Before and following ADT, serum and 24-h urinary samples were collected. Primary endpoints were changes in calcium-phosphate homeostasis and bone biomarkers. Of the 89 randomised patients, 43 in the degarelix+apalutamide and 44 patients in the degarelix+placebo group were included in this substudy. Serum corrected calcium levels increased similarly in both treatment arms (mean difference+0.04mmol/L, 95% confidence interval, 0.02; 0.06), and parathyroid hormone and 1,25-dihydroxyvitamin D3 levels decreased. Bone resorption markers increased, and stable calcium isotope ratios reflecting net bone mineral balance decreased in serum and urine similarly in both groups. This exploratory substudy suggests that 12 weeks of ADT in non-metastatic PCa patients results in early bone loss. Additional treatment with ARSI does not seem to more negatively influence bone loss in the early phase. Future studies should address if these early biomarkers are able to predict fracture risk, and can be implemented in clinical practice for follow-up of bone health in PCa patients under ADT. Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven.

FRI684 So Strong Yet So Fragile: Bilateral Periprosthetic Fractures On Denosumab

Abstract Disclosure: A. Syeda: None. F.S. Mirza: None. Background: Denosumab (DN) is a potent antiresorptive and has been associated rarely with atypical femoral fractures. We hereby report the first case of simultaneous bilateral femoral periprosthetic fractures (PPF) while on DN therapy (DNT). Clinical Case: A 78-year-old female with severe osteoporosis on DNT presented in January 2023 with bilateral femoral PPF after a mechanical fall whereby she tripped and landed on her knees. The patient had initially presented to us in late 2012. Treatment history included alendronate (ALN) for 5 years, on drug holiday since 2010. She underwent bilateral knee replacement surgeries in 2012 and DNT was started in 2013 after initial evaluation. She also had primary biliary cirrhosis, and although bone density (BD) improved on DNT, she exhibited escape from DN mediated suppression of bone resorption possibly related to the liver disease that was previously reported (1). DNT was stopped 5 years later when spine BD improved to osteopenic range and ALN 70 mg weekly was started. 1 year later, bone resorption markers were still elevated and zoledronic acid was substituted for ALN. She fell and had a pubic ramus fracture 11 months later. BD showed a 6% decrease for mean total hip and baseline forearm BD showed T-score of -3.7 on the right. DNT was restarted in December 2020 and continued every 6 months. Her health continued to deteriorate over next two years, with increase in LFTS, new anemia and thrombocytopenia due to a combination of myelodysplastic syndrome and splenomegaly. She also needed transcatheter aortic valve replacement for worsening CHF. She tripped and fell in January 2023. X-ray showed acute supracondylar bilateral PPF with comminution. She was high risk for anesthesia and anticoagulation was withheld due to a history of thrombocytopenia and gastrointestinal bleeding. Prior to the anticipated orthopaedic procedure, the patient developed severe hypotension and a rapid drop in hematocrit due to hemorrhagic shock. The family had requested DNR due to the multitude of medical issues. Conclusion: Occasional PPF have been reported in the setting of DNT, which may reflect the severity of osteoporosis. Altered stress distribution and decreased tensile strength of the bone secondary to screw/pin placement are thought to contribute to PPF, although the occurrence of PPF as an unusual presentation of an AFF cannot be excluded. Contribution of other comorbidities to poor bone quality may also have contributed to the bilateral PPF with poor outcome in our patient. 1. Vedere, T.R. and Mirza, F.S., 2017, April. Escape from Denosumab Mediated Suppression of Bone Resorption in Primary Biliary Cirrhosis. In 99th Annual Meeting of the Endocrine Society. Endocrine Society. Presentation: Friday, June 16, 2023

THU445 Complicated Course And Management After Denosumab Discontinuation: A Case Report

Abstract Disclosure: I. Arora: None. L. Ceglia: None. Background: Discontinuation of denosumab (DMAb) can lead to rapid bone loss and sometimes multiple vertebral fractures (VFx). Here we present such a case and related challenges in management. Case: A 56-year-old perimenopausal female presented for management of osteoporosis (OP) complicated by multiple VFx following a missed dose of DMAb in 8/2020. Past bone health history was notable for treatment with alendronate for approximately 11 years as a premenopausal woman. During a drug “holiday” in 2015, she was found to have a decline in bone mineral density (BMD). She was advised to start treatment with DMAb in 8/2016. She was adherent to DMAb injections for 4 years but missed a dose in 8/2020 due to the COVID-19 pandemic. In 1/2021, she developed back pain with no trauma and was diagnosed with VFx of T7, T10 and T12. She underwent vertebroplasty of all 3 vertebrae by 2/2021. DMAb was resumed in 2/2021 and 8/2021. Labs were only notable for hypercalciuria for which hydrochlorothiazide (HCTZ) was initiated. In 11/2021 she presented with new symptomatic VFx of T5, T9 and T11. In 12/2021 (3 weeks post 3 new VFx), serum fasting C-telopeptide (CTX) was 79 pg/mL. Teriparatide or abaloparatide were avoided due to hypercalciuria and potential BMD losses with this transition. Thus in 1/2022, she started romosozumab (ROMO) in an attempt to prevent new VFx. CTX was initially 78 pg/mL and rose rapidly over 3 months to 325 pg/mL with new back pain in 4/2022. No new VFx were detected; however, ROMO was discontinued due to the rise in CTX level. In 5/2022, she received a dose of zoledronic acid (ZOL). It suppressed CTX from 325 to 131 pg/mL by 6/2022. She received another 2 doses of ZOL in 8/2022 and 11/2022 due to rebound rises in CTX. Of note, as she reported ongoing menopausal complaints, transdermal low-dose estradiol therapy was started in 11/2022. She has not had a new VFx in more than 1 year. Hypercalciuria persisted throughout 2022 requiring rising doses of (HCTZ). DXA in 12/2022 was stable vs. 12/2021 without evidence of significant BMD loss. Discussion: This case not only highlights the known risk for multiple VFx in a patient discontinuing long-term DMAb treatment (4 years), but also the risks for such VFx complications in women of younger age during menopausal transition and a history of vertebroplasty. In addition, this report does not support transitioning from long-term DMAb to ROMO in order to prevent a rapid increase in the bone resorption marker, CTX. Rather, treatment with ZOL every 12 weeks based on frequent CTX monitoring successfully maintained BMD stable following long-term DMAb discontinuation. Presentation: Thursday, June 15, 2023

Yunvjian decoction attenuates lipopolysaccharide-induced periodontitis by suppressing NFκB/NLRP3/IL-1β pathway

Ethnopharmacological relevanceYunvjian decoction (YNJ) is a traditional Chinese herbal prescription that has been used in the clinical treatment of periodontitis. However, the underlying molecular mechanism of YNJ in the periodontitis treatment is not well understood. Aim of the studyThe purpose of this study was to evaluate the therapeutic effects of YNJ against periodontitis and its underlying molecular mechanisms. Materials and methodsOrthodontic ligation and lipopolysaccharide (LPS)-induced periodontitis rat model was established. YNJ groups were gavaged with YNJ decoction (5 g/kg/d or 10 g/kg/d) for four months. The rats in positive control group were gavaged with metronidazole (MDZ, 100 mg/kg/d) for four months. The maxilla was scanned by micro-computed tomography. The chemical compositions of YNJ were identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry. The molecular mechanism of YNJ were predicted using network pharmacological analysis and validated using immune-staining and Western blot. ResultsYNJ treatment decreased the distance between cementoenamel junction and alveolar bone crest on the sagittal slide of the periodontitis rats. Western blot showed YNJ downregulated the protein levels of the bone resorption marker (receptor activator of nuclear factor-κB ligand), while upregulated the levels of the bone formation markers (bone morphogenetic protein 2, runt-related transcription factor 2, alkaline phosphatase, and osteoprotegerin) in alveolar bone of the periodontitis rats. Hematoxylin and eosin, immunohistochemical staining, and Western blot analysis indicated that YNJ attenuated the inflammation and decreased the levels of interleukin-6 and tumor necrosis factor-α in the alveolar bone. In addition, a total of 61 compounds were identified from YNJ. Network pharmacology indicated that the nucleotide binding oligomerization domain-like receptor signaling pathway was the main pathway for YNJ in the treatment of periodontitis. The experiments confirmed that YNJ administration inhibited LPS induced-pyroptosis in alveolar bone through suppressing the phosphorylation of nuclear factor κB, reduced expression of NOD-like receptor family pyrin domain containing 3, and Caspase-1, subsequently suppressing the interleukin-1β secretion. ConclusionYNJ is an effective therapeutic strategy for periodontitis and acts by inhibiting pyroptosis and NFκB/NLRP3/IL-1β pathway in alveolar bone.

Bone health in SATB2-associated syndrome: Results from a large prospective cohort and recommendations for surveillance.

Alterations in SATB2 result in SATB2-associated syndrome (SAS; Glass syndrome, OMIM 612313), an autosomal dominant multisystemic disorder predominantly characterized by developmental delay, craniofacial anomalies, and growth retardation. The bone phenotype of SAS has been less explored until recently and includes a variety of skeletal deformities, increased risk of low bone mineral density (BMD) with a propensity to fractures, and other biochemical abnormalities that suggest elevated bone turnover. We present the results of ongoing surveillance of bone health from 32 individuals (47% females, 3-18 years) with molecularly-confirmed SAS evaluated at a multidisciplinary clinic. Five individuals (5/32, 16%) were documented to have BMD Z-scores by DXA scans of -2.0 SD or lower and 7 more (7/32, 22%) had Z-scores between -1 and - 2 SD at the lumbar spine or the total hip. Alkaline phosphatase levels were found to be elevated in 19 individuals (19/30, 63%) and determined to correspond to bone-specific alkaline phosphatase elevations when measured (11/11, 100%). C-telopeptide levels were found to be elevated when adjusted by age and gender in 6 individuals (6/14, 43%). Additionally, the two individuals who underwent bone cross-sectional geometry evaluation by peripheral quantitative computed tomography were documented to have low cortical bone density for age and sex despite concurrent DXA scans that did not have this level of decreased density. While we could not identify particular biochemical abnormalities that predicted low BMD, the frequent elevations in markers of bone formation and resorption further confirmed the increased bone turnover in SAS. Based on our results and other recently published studies, we propose surveillance guidelines for the skeletal phenotype of SAS.