Procollagen Type I N Propeptide Research Articles

Associations of AMH in mid-reproductive years with bone mineral density and turnover markers in mid-life.

Concentration of circulating anti-Müllerian hormone (AMH) predicts short-term (3-5 years) bone loss around menopause. Whether AMH during mid-reproductive years predicts bone health over a decade later is unknown. To study the association of AMH levels in mid-reproductive years with bone density and turnover biomarkers measured after ∼14 years of follow-up. We assessed plasma AMH in 2003-2006 (mean 37.0 years, SD 5.1) among 450 parous women (71% White) in a US longitudinal cohort, and bone mineral density (BMD; spine, hip, and femoral neck, measured by dual-energy X-ray absorptiometry) in 2017-2021 (mean 51.0 years, SD 5.1). Secondary outcomes were plasma levels of procollagen type I N-propeptide (PINP) and C-terminal telopeptide I (CTX-I). In linear regression models adjusted for demographics and lifestyle, compared to women with AMH >3.5 ng/mL, those with AMH <1.0 ng/mL had lower BMD (g/cm2) at follow-up (beta [95% CI]: spine: -0.06 [-0.10, -0.02]; hip: -0.05 [-0.08, -0.02]; femoral neck: -0.03 [-0.06, 0.00]) and higher bone turnover markers (beta [95% CI]: PINP: 0.36 SD [0.10, 0.63]; CTX-I: 0.34 SD [0.07, 0.60]). The association of AMH with spine BMD was more pronounced among post-menopausal women, in contrast to associations with bone turnover markers which were more pronounced among women who had not yet reached menopause. The associations between AMH and BMD were primarily mediated by menopausal status at follow-up. Lower AMH during mid-reproductive years is associated with lower BMD and higher bone turnover 14 years later. Ovarian reserve during mid-reproductive years may be a valuable predictor of long-term bone health.

Biomarkers of bone metabolism in [223Ra] RaCl2 therapy - association with extent of disease and prediction of overall survival

BackgroundThe alpha-emitting radionuclide therapy [223Ra]RaCl2 (Radium-223) improves overall survival (OS) and time to symptomatic skeletal event (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC). Evidence suggests that the effect of Radium-223 is partly exerted through an impact on the surrounding bone matrix. We hypothesized that bone metabolism markers (BMM) could provide predictive information regarding response to Radium-223. Accordingly, the aim of this study was to investigate changes in BMM during Radium-223 therapy and evaluate association with clinical outcome.MethodsProspective study of BMM in patients with mCRPC receiving Radium-223. Blood samples were collected before each administration of Radium-223 and the following BMM were quantified; bone-specific alkaline phosphatase (BALP), osteocalcin, procollagen type I N-propeptide (PINP), C-terminal telopeptide of type I collagen (CTX), C-terminal cross-linking telopeptide of type I collagen generated by matrix metalloproteinases (CTX-MMP), tartrate-resistant acid phosphatase isoform 5b (TRACP5b), receptor-activated nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. Clinical outcomes were scintigraphic progression during/after therapy, change in bone scan index (BSI), occurrence of SSE, and OS.ResultsA total of 55 mCRPC patients were included. There was a significant linear association between skeletal extent of disease and CTX-MMP, PINP, BALP, and osteocalcin. No significant association between dynamics in BSI and BMM were detected. Median OS for the cohort was 14 months (95% CI: 10.7–16.8). Baseline levels of Log2-CTX-MMP (HR = 2.15 (95%CI: 1.1–4.1)) and Log2-BALP (HR = 1.59 (95%CI: 1.1–2.1)) were associated with OS. Patients with increasing CTX-MMP during therapy had significantly shorter OS (Median OS = 4 mo. (95%CI: 2.3–5.7)) than patients with stable or decreasing CTX-MMP (Median OS = 12 mo. (95%CI: 10.1–13.9), P < 0.001).ConclusionBMM are significantly associated with scintigraphic extent of skeletal disease and OS in patients with mCRPC. Particularly, the bone resorption marker CTX-MMP is a promising surrogate marker for prediction of outcome in patients receiving Radium-223 therapy and could potentially improve selection of patients for therapy and assessment of response.Trial registrationClinicaltrials.gov, NCT03247010. Registered 10th of August 2017, https://clinicaltrials.gov/study/NCT03247010?term=NCT03247010&rank=1.

Changes in Serum Concentrations of Bone Turnover Markers in Healthy Pregnant Women.

Changes in bone metabolism during pregnancy have not received sufficient attention because of the lack of effective screening tools. Bone turnover markers (BTMs) could reflect the changes of bone metabolism. Currently, reference intervals for bone metabolism during normal pregnancy are inconclusive. This study aimed to determine reference intervals for BTMs in pregnant women taking prenatal care and to facilitate clinical research on diseases affecting bone metabolism during pregnancy. We surveyed 120 low-risk pregnant women attending routine antenatal care from January 2020 to March 2020. The serum levels of procollagen type I N-propeptide (PINP), N-terminal osteocalcin (N-MID), and C-terminal telopeptide of type I collagen (β-CTX) were measured in the first trimester (<13 weeks), second trimester (14-27 weeks), and third trimester (>28 weeks). Reference intervals for BTMs during pregnancy were analyzed. The Kruskal-Wallis test and paired t-test are used to analyze differences between groups. Spearman correlation coefficients expressed the measure of linear association. The bone resorption marker β-CTX in third trimester increases compared to the first trimester and the second trimester (P < 0.001, P < 0.001). The bone formation markers PINP and N-MID were decreased from the first trimester to the second trimester (P = 0.01, P < 0.001) and then raised from the second trimester to the third trimester (P < 0.001, P < 0.001). Two indices of bone turnover rate, β-CTX/PINP and β-CTX/N-MID, were increased from the first trimester to the second trimester (P < 0.001, P < 0.001) and then decreased from the second trimester to the third trimester (P = 0.02, P < 0.001). This study established reference intervals for BTMs in pregnant women and observed the changes in BTMs during the different trimesters of pregnancy. The present findings can help in clinical monitoring of the effects of pregnancy diseases on the bone metabolism of pregnant women.

Bone turnover biomarkers predict one-year all-cause mortality and walking ability in geriatric hip fracture patients.

To investigate the utility of serum C-terminal cross-linking telopeptides (β-CTX) and procollagen type I N propeptide (PINP) for predicting one-year mortality and walking ability in Chinese geriatric hip fracture patients who underwent surgical interventions. Elderly patients (≥ 60 years) who underwent surgical interventions for unilateral low-energy hip fracture from 2015 to 2020 in our center were included. Demographic data was retrospectively retrieved from the electronic medical database. The PINP and β-CTX concentrations were measured before the surgery. The patients were divided into two groups according to the outcome of mortality and walking ability after hip surgery, respectively. β-CTX and PINP were divided into four grades based on quartiles [Quartile(Q)1-4] for further analysis. All the variables with p < 0.1 in univariable analysis were included in a multivariable model. In univariable analysis, the levels of serum β-CTX (p = 0.007) and PINP (p = 0.025) was associated with one-year mortality, while the association between levels of serum β-CTX (p = 0.072) or PINP (p = 0.055) with one-year disability was marginally significant. After adjustment for confounders, the relative risk [OR (95 % CI), Q4 v sQ1, p-value] of one-year mortality and one-year disability were 7.28 (2.08-29.78, p = 0.003) and 3.97 (1.44-11.69, p = 0.009) for β-CTX and 5.87 (1.70-23.80, p = 0.008) and 3.48 (1.30-9.93, p = 0.016) for PINP, respectively. The coefficient of determination, AUC and bias-corrected C-index of predictive models based on previously reported predictors were significantly improved after integrating β-CTX or PINP. Higher serum β-CTX and PINP are independently associated with an increased risk of one-year mortality and disability in patients with hip fractures. The application of BTMs improves the performance of currently available predictive models.

High Incidence of Vitamin D Deficiency Among Patients Undergoing Hematopoietic Stem Cell Transplant and a Single Ultra-High Dose Vitamin D Replacement

Introduction: Vitamin D involves in several important human physiologic pathways from bone metabolism to inflammation and immune regulation. Patients who undergo hematopoietic stem cell transplant (HSCT) are at risk of developing vitamin D deficiency from various mechanisms and replacement of vitamin D in these patients can be challenging according to several reasons. In addition, vitamin D may potentially affect outcomes, overall health and quality of life after HSCT. An ultra-high dose vitamin D replacement was previously explored in pediatric HSCT patients but has never been investigated in adult patient population. In this study, we explored the incidence of vitamin D deficiency, the safety and efficacy of a single ultra-high dose vitamin D replacement including its effect on bone health among adult patients with hematologic malignancy undergoing HSCT. Patients and Methods: First, we looked at the retrospective cohort of patients who underwent HSCT between January 2017 and August 2022 to explore the incidence of vitamin D deficiency (25-hydroxy vitamin D level &amp;lt;20 ng/mL) in Thailand. Subsequently, we prospectively included adult patients with hematologic malignancy undergoing both autologous (ASCT) and allogeneic HSCT (alloHSCT) from September 2022 to June 2023. All patients received a single ultra-high dose vitamin D on the day of admission prior to the initiation of conditioning regimens. We reported the safety and efficacy of a single ultra-high dose vitamin D (Ergocalciferol; Vitamin D2) replacement as calculated by weight and pre-transplantation vitamin D level among these patients using the Stoss protocol previously described. The effect of an ultra-high dose vitamin D on bone turnover was also monitored. Results: In the retrospective cohort, 229 patients underwent HSCT (146 ASCT and 83 alloHSCT). Vitamin D deficiency was observed in 147 patients (64.6%) including 91 (62.3%) ASCT and 56 (67.5%) alloHSCT. The median 25-hydroxy (25-OH) vitamin D level was 17.6 (4.0-86.3) ng/mL comparable between autologous and allogeneic patients. In the prospective cohort, 45 patients underwent HSCT (27 ASCT and 18 alloHSCT). The median age of patients at the time of HSCT was 49 (23-67) years with 18 patients (40%) being male. The median pre-transplant 25-OH vitamin D level was 20.2 ng/mL with 22 patients (48.9%) (13 ASCT, 9 alloHSCT) meeting the criteria of vitamin D deficiency. The median dose of vitamin D2 used was 500,000 (300,000-600,000) IU. At day +28 post-HSCT, 40% of patients were able to attain 25-OH vitamin D level above 30 ng/mL comparable between ASCT and alloHSCT but significantly higher compared to the retrospective cohort. The time to neutrophil and platelet engraftment were 13 (9-26) days and 14 (9-33) days, comparable between the controlled retrospective cohort and high dose replacement prospective cohort. The median levels of parathyroid hormone (PTH) and bone turnover markers including osteocalcin, β-CrossLaps (β-CTx), and procollagen type I N-propeptide (PINP) at day+28 was 45.4 (19.4-152.2) pg/mL, 11.3 (6.0-16.8) ng/mL, 0.79 (0.1-13.0) ng/ml and 43.7 (19.7-133.7) mcg/L, respectively. Among patients who underwent alloHSCT, the incidence of cytomegalovirus reactivation and acute graft versus host disease was 72.2% and 11.1% (no grade 3-4), respectively. Figure 1 shows the kinetic of serum 25-OH vitamin D, Calcium, β-CTx and PINP of patients in the prospective cohort from baseline to day +28 post-HSCT. At all timepoints (day 0, +7, +14, +21, +28), the median level of vitamin D level was significantly higher whereas the median serum PINP level was significantly lower compared to the baseline level. There was no occurrence of hypercalcemia or bony events during the time of the study. Conclusion: Our study highlights a high incidence of vitamin D deficiency in HSCT patients. Utilizing a single ultra-high dose vitamin D is an effective and safe approach to replace vitamin D in adult patients undergoing HSCT. A high percentage of patients could maintain adequate vitamin D level during post-transplant period. PINP level was sustainably decreased after vitamin D replacement indicating a lower bone resorption. Whether this approach will translate into improved immune function, long-term bone health and outcomes compared to the conventional replacement strategy warrants further exploration in prospective randomized clinical trials.

THU426 Randomized Controlled Trial Comparing The Efficacy Of Teriparatide, Zoledronate And Denosumab In Postmenopausal Women With Type 2 Diabetes Mellitus At High Risk Of Fragility Fractures: 6-month Interim Analysis Of HR-pQCT Parameters

Abstract Disclosure: R. Pal: None. T.N. Prasad: None. S.K. Bhadada: None. V. Singla: None. S. Ram: None. N. Aggarwal: None. A. Kumar: None. People with type 2 diabetes (T2D) are at high-risk of fragility fractures, however, there are no randomised controlled trials (RCTs) evaluating the efficacy/safety of anti-osteoporosis drugs as a primary endpoint in T2D (1). To address this lacuna, we conducted a pilot prospective, open-labeled, blinded-end point (PROBE) RCT (CTRI/2022/02/039978) wherein consecutive postmenopausal female (≥ 50 years) with T2D (duration ≥ 5 years) were screened. Subjects with HbA1c 7-10%, eGFR &amp;gt; 45 ml/min/1.73 m2 and prior history of vertebral (clinical/morphometric), hip, radius, humeral fragility fracture or at high-risk of fragility fractures [defined as areal bone mineral density (BMD) T-score (adjusted for diabetes) at lumbar spine/femoral neck ≤ -2.5 and high FRAX score] and without any secondary cause of osteoporosis were randomised in staggered fashion in a 1:1:1:1 ratio to receive either daily teriparatide, yearly zoledronate, biannually denosumab (in addition to standard of care, i.e., calcium 1000 mg/day and cholecalciferol 1000 IU/day) or only standard of care (control). The primary end points were change in areal BMD and frequency of incident fractures at 18 months. The secondary end point was change in HR-pQCT parameters measured at distal radius and distal tibia (XtremeCT II, SCANCO Medical AG, Switzerland) at 6 and 18 months.Out of 412 participants who were screened, 104 subjects were randomized to any of the 4 arms. Out of these 104 subjects, 53 have completed 6 months of follow-up (teriparatide n=14, zoledronate n=14, denosumab n=15, control n=10). There were no statistically significant differences in age, HbA1c, eGFR, calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone, procollagen type I N-propeptide (PINP), C-terminal telopeptide (CTX), areal BMD, trabecular bone score (TBS), FRAX score or HR-pQCT parameters between the 4 groups at randomisation. At 6 months, there was no significant difference in HbA1c between the 4 groups; PINP and CTX rise was significantly higher in teriparatide arm compared to zoledronate, denosumab or control arms. With regard to HR-pQCT, there were no statistically significant differences in total [total volumetric BMD (vBMD), bone volume fraction], cortical (vBMD, thickness, porosity, pore diameter), or trabecular (vBMD, thickness, number, separation) bone properties at the distal radius and distal tibia between the 4 arms at 6 months of follow-up. To conclude, zoledronate, denosumab or teriparatide were unable to induce any significant microarchitectural changes than standard of care in postmenopausal women with T2D at high-risk of fragility fractures following 6 months of treatment. Longer duration of treatment and follow-up of the cohort is required to arrive at robust conclusions. Reference: (1) Pal et al., Bone fragility in type 2 diabetes mellitus: a lot left to explore. Nat Rev Endocrinol. 2022;18:651-651 Presentation: Thursday, June 15, 2023

Profile of matrix metalloproteinase activity, markers of collagen and elastin degradation and remodeling during pregnancy, delivery, and puerperium in pelvic organ prolapse 3 months after childbirth

Background: This study aims to assess the condition of pelvic organ prolapse related to changes in matrix metalloproteinase activity, elastin degradation and markers of collagen, and remodeling observed during pregnancy, childbirth, and the puerperal period 3 months postpartum. This study included 39 primigravida women who underwent vaginal delivery with a gestational age &gt;36 weeks. This study conducted laboratory tests using blood and urine samples including procollagen type I N-propeptide (PINP), procollagen type-III N-propeptide (PIIINP), telopeptide carboxyl-terminal collagen type I (ICTP), matrix metalloproteinase-9 (MMP). -9), desmosin, and tropoelastin. The second and third blood samples will be examined 24-48 hours postpartum and 6 weeks postpartum. Method: The Mann-Whitney test and Repeated ANOVA were used to assess the median differences between biomarkers. Results: In the pelvic floor dysfunction and control groups, a significant relationship was found between serum MMP-9 levels 6 weeks postpartum (p=0.025). There were changes in biomarker levels of collagen and elastin during pregnancy, post-partum, and six weeks postpartum. The amount of degradation (MMP-9) seems to be correlated with the event of POP after childbirth. Conclusion: There were changes in the biomarker levels of collagen and elastin from pregnancy, post-partum, and six weeks postpartum. In addition, the difference was significant in MMP-9 level six weeks after postpartum in POP group compare to control.

Impact of Alcohol on Bone Health in People Living With HIV: Integrating Clinical Data From Serum Bone Markers With Morphometric Analysis in a Non-Human Primate Model.

People living with HIV (PLWH) represent a vulnerable population to adverse musculoskeletal outcomes due to HIV infection, antiretroviral therapy (ART), and at-risk alcohol use. Developing measures to prevent skeletal degeneration in this group requires a grasp of the relationship between alcohol use and low bone mass in both the PLWH population and its constituents as defined by sex, age, and race. We examined the association of alcohol use with serum biochemical markers of bone health in a diverse cohort of PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) study. To explore the effects of alcohol on bone in the context of HIV and ART and the role of estrogen, we conducted a parallel, translational study using simian immunodeficiency virus (SIV)+/ART+ female rhesus macaques divided into four groups: vehicle (Veh)/Sham; chronic binge alcohol (CBA)/Sham; Veh/ovariectomy (OVX); and CBA/OVX. Clinical data showed that both osteocalcin (Ocn) and procollagen type I N-propeptide (PINP) levels were inversely associated with multiple measures of alcohol consumption. Age (>50 years) significantly increased susceptibility to alcohol-associated suppression of bone formation in both female and male PLWH, with postmenopausal status appearing as an additional risk factor in females. Serum sclerostin (Scl) levels correlated positively with measures of alcohol use and negatively with Ocn. Micro-CT analysis of the macaque tibias revealed that although both CBA and OVX independently decreased trabecular number and bone mineral density, only OVX decreased trabecular bone volume fraction and impacted cortical geometry. The clinical data implicate circulating Scl in the pathogenesis of alcohol-induced osteopenia and suggest that bone morphology can be significantly altered in the absence of net change in osteoblast function as measured by serum markers. Inclusion of sophisticated tools to evaluate skeletal strength in clinical populations will be essential to understand the impact of alcohol-induced changes in bone microarchitecture. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Effects of weight loss on bone turnover, inflammatory cytokines, and adipokines in Chinese overweight and obese adults

PurposePlenty of studies have examined the long term effect of weight loss on bone mineral density. This study aimed to explore the effects of 10% weight loss on early changes in bone metabolism as well as the possible influencing factors.MethodsOverweight and obese outpatients (BMI > 24.0 kg/m2) were recruited from the nutrition clinic and followed a calorie-restricted, high-protein, low-carbohydrate diet program. Dietary intake, body composition, serum procollagen type I N-propeptide (PINP), β-Crosslaps, PTH, 25(OH) VitD, a series of inflammatory cytokines and adipokines were measured for the participants before starting to lose weight and after 10% weight loss (NCT 04207879).ResultsA total of 75 participants were enrolled and 37 participants achieved a weight loss of at least 10%. It was found that PINP decreased (p = 0.000) and the β-Crosslaps increased (p = 0.035) in female participants. Decreases in PTH (p = 0.001), serum IL-2 (p = 0.013), leptin (p = 0.001) and increases in 25(OH) VitD (p = 0.001), serum ghrelin (p = 0.033) were found in 37 participants after 10% of their weight had been lost. Change in PINP was detected to be significantly associated with change in lean body mass (r = 0.418, p = 0.012) and change in serum ghrelin(r = − 0.374, p = 0.023).ConclusionsBone formation was suppressed and bone absorption was increased in female subjects after a 10% weight loss. Bone turnover was found to be associated with lean body mass and affected by the circulating ghrelin level.

Impact of Daratumumab Monotherapy on Bone Metabolism Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least Two Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor: Outcomes of the Phase 2 Rebuild Study

Impact of Daratumumab Monotherapy on Bone Metabolism Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least Two Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor: Outcomes of the Phase 2 Rebuild Study

Age-related trends and reference intervals of cross-linked C-telopeptide of type I collagen and procollagen type I N-propeptide from a reference population of Sri Lankan adult women.

This study was performed to establish age-related reference intervals for bone resorption marker; cross-linked C-telopeptide of type I collagen (CTX) and bone formation marker; procollagen type I N-propeptide (PINP) in a group of Sri Lankan adult women. Adult women (n = 347) aged 20-70years were recruited using age-stratified random sampling technique and categorized into age groups by decades. Serum CTX and PINP concentration were measured using enzyme-linked immunosorbent assay (ELISA). The geometric mean (95% confidence interval) and 2.5th and 97.5th percentiles were calculated. ANOVA was used to compare the means between groups. Mean CTX levels were relatively low and remained unchanged between 20 and 49years. After the age of 49years, mean CTXconcentration elevated significantly until the age of 70years (43%, p < 0.001). Mean PINP concentrations were not significantly different between age categories (p > 0.05). Reference intervals of CTX and PINP were based on 2.5th and 97.5th percentile values. Reference intervals of CTX for the age groups of 20-29, 30-39, 40-49, 50-59, and 60-70years were 0.19-0.97ng/mL, 0.18-0.95ng/mL, 0.20-1.29ng/mL, 0.17-2.20ng/mL, and 0.17-2.85ng/mL respectively. Reference intervals of PINP for the same age groups were 118-810pg/mL, 119-772pg/mL, 116-645pg/mL, 108-684pg/mL, and 108-715pg/mL respectively. In Sri Lanka, bone turnover markers are not used in evaluating patients mainly due to lack of normative data. These values can be used as reference data for women in this age group.

Clinical significance of serum transforming growth factor-β1 and procollagen type I N-propeptide in post-tuberculosis tracheobronchial stenosis.

Non-invasive strategies for monitoring post-tuberculosis (TB) tracheobronchial stenosis (PTTS) are clinically important but currently lacking. Transforming growth factor-β1 (TGF-β1) and procollagen type I N-propeptide (PINP) have been identified as markers of fibrosis. The present study aimed to investigate the clinical significance of serum TGF-β1 and PINP in PTTS. Serum samples were collected from 119 patients with tracheobronchial TB after the condition was treated for at least 6 months (59 patients with airway stenosis and 60 patients with no stenosis). Serum TGF-β1 and PINP levels were measured using ELISA and compared between the groups. Relationships between serum TGF-β1 and PINP levels and clinical characteristics, interventional bronchoscopy and outcomes of airway stenosis were analysed. The correlation between TGF-β1 and PINP, and their diagnostic efficacy for airway stenosis were also analysed. The TGF-β1 and PINP levels in the airway stenosis group were higher than those in the non-stenosis group. Furthermore, airway stenosis with atelectasis or mucus plugging was associated with higher TGF-β1 levels, and airway stenosis with atelectasis, mucus plugging, right main bronchus stenosis or severe airway tracheal stenosis was associated with higher PINP levels. In addition, TGF-β1 and PINP levels increased after interventional bronchoscopy therapy and airway stenosis with recurrent stenosis was associated with higher baseline levels of both markers. Finally, TGF-β1 levels were positively correlated with PINP levels in patients with airway stenosis. The area under the receiver operating characteristic curve of TGF-β1 and PINP for distinguishing airway stenosis from non-stenosis cases was 0.824 (95% CI: 0.748-0.900) and 0.863 (95% CI: 0.796-0.930), respectively. Therefore, TGF-β1 and PINP are potential biomarkers that may be useful for diagnosing and monitoring PTTS.

Age- and sex-specific concentrations of bone remodeling markers in healthy Indian adults with and without vitamin D deficiency.

The present study was undertaken to generate data on age- and sex-specific concentrations of serum procollagen type I N-propeptide (PINP) and type I collagen C-telopeptide (CTX) in healthy Indian adults with and without vitamin D deficiency. Apparently, healthy subjects aged ≥ 20 years with no prior co-morbidities were recruited from thecommunity by door-to-door surveys. Provisionally eligible participants underwent blood sampling after overnight fast. Individuals with biochemical abnormalities that could potentially affect bone remodeling were excluded. However, subjects with vitamin D deficiency were not excluded. Serum total PINP and β-CrossLaps (CTX) were measured using electro-chemiluminescence immunoassay. After exclusion, 677 subjects were enrolled (M:F = 2.5:4.2, mean age = 45.0 years). Median serum PINP and CTX were 55.78 ng/ml (40.27-71.70) and 0.356 ng/ml (0.238-0.499), respectively. There was no difference in PINP/CTX between men and women or between premenopausal and postmenopausal women. Decade-wise distribution of PINP/CTX showed that maximum values were attained in 3rd decade; subsequently, in men, levels declined with age while in women, there was a peak in the6th decade coinciding with theearly years of menopause. Vitamin D deficiency and severe vitamin D deficiency were seen in 417 (61.5%) and 259 subjects (38.2%), respectively. There was no significant difference in PINP/CTX in subjects with and without vitamin D deficiency. The present study has allowed us to generate data on serum concentrations of PINP/CTX in a diverse group of healthy community-dwelling Indian adults with varying serumvitamin D levels. It might aid in monitoring response to anti-osteoporotic therapy amongst native Indians.

The Role of PINP in Diagnosis and Management of Metabolic Bone Disease.

Serum procollagen type I N-propeptide (PINP) is designated the reference marker of bone formation in osteoporosis; the reference marker for resorption is C-terminal telopeptide of type I collagen (CTX). PINP has very low circadian and biological variation, is not affected by food intake, and is very stable in serum after venepuncture. The two automated commercial assays for PINP provide similar results in subjects with normal renal function, allowing reference intervals to be used interchangeably. Bone turnover markers (BTM) are currently not recommended for fracture risk assessment and therefore not included in fracture risk calculators. In the management of osteoporosis, the main utility of BTM including PINP is for monitoring therapy, both antiresorptive as well as anabolic agents; monitoring is thought to help improve adherence. PINP as well as CTX may also be used in assessing offset of drug action following a pause in bisphosphonate therapy, to help decide when to re-instate therapy, or following cessation of denosumab therapy to assess efficacy of follow-on bisphosphonate therapy. PINP may also be used in the diagnosis of Paget's disease of bone as well as in monitoring response to therapy and for recurrence. Although BTM other than bone alkaline phosphatase are currently not recommended for use in metabolic bone disease of chronic kidney disease, PINP measured by assays specific to the intact molecule has potential in this condition. Further studies are needed to examine this area, as well as in malignant bone disease.

Analytical considerations and plans to standardize or harmonize assays for the reference bone turnover markers PINP and β-CTX in blood

Procollagen type I N-propeptide (PINP) and the C-terminal telopeptide of type I collagen (β-CTX) in blood have been designated as reference bone turnover markers in osteoporosis by the International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The IFCC Committee on Bone Metabolism (C-BM) has examined current commercial assays and performed a multicentre study to examine the agreement between assays for PINP and β-CTX in serum and plasma. The results of these studies will inform our work towards the harmonization of PINP assays and the standardization of β-CTX assays in blood, with the development of common calibrators and reference measurement procedures in collaboration with the reagent manufacturing industry. Successful achievement of these goals will help develop universally acceptable practice guidelines for the management of osteoporosis with the inclusion of common reference intervals and treatment targets for PINP and β-CTX.

Bone Turnover Markers Including Undercarboxylated Osteocalcin Are Associated With Mortality Risk in Older Men

ABSTRACTOsteocalcin in its undercarboxylated form (ucOC) may influence diabetes risk; however, its relationship with all‐cause and cause‐specific mortality is unclear. Whether other bone turnover markers (BTMs) are associated with mortality risk differently from ucOC also remains uncertain. Our aim was to determine associations of serum ucOC with all‐cause and cause‐specific mortality and compare these with the corresponding associations of serum total osteocalcin (TOC), procollagen type I N‐propeptide (PINP), and collagen type 1 C‐terminal cross‐linked telopeptide (CTX) in older men. We conducted a prospective cohort study of 3871 community‐dwelling men, aged 77.0 ± 3.6 years at baseline, followed for a median of 12.3 years. Exposure variables were ucOC, TOC, PINP, and CTX concentrations assayed in serum. Outcomes were incidence of all deaths and deaths due to cardiovascular disease (CVD) or cancer, ascertained using death registry data. Cox regression analyses adjusted for cardiovascular risk factors and prevalent CVD and for prevalent cancer in analyses of cancer‐related mortality. Higher concentrations of ucOC, PINP, and CTX were associated with all‐cause mortality (hazard ratio [HR] per 1 standard deviation increase: ucOC 1.12, 95% confidence interval [CI] 1.06–1.18, p < 0.001; PINP HR = 1.06, 95% CI 1.01–1.11, p = 0.009; CTX HR = 1.13, 95% CI 1.08–1.19, p < 0.001), but TOC was not associated. Similar results were found after excluding men with an incident fracture during follow‐up. Higher ucOC and CTX were associated with CVD mortality (ucOC HR per 1 SD increase 1.13, 95% CI 1.05–1.22, p = 0.001; CTX HR = 1.12, 95% CI 1.04–1.20, p = 0.003), but this result was not significant in competing risks analysis. Higher CTX was also associated with cancer mortality (HR = 1.12, 95% CI 1.01–1.23, p = 0.024). In conclusion, in older men, higher bone turnover, assessed by BTMs including ucOC, is a biomarker for all‐cause mortality risk. Undercarboxylated osteocalcin was a more informative biomarker for this outcome than TOC. Higher CTX was associated with all‐cause and cancer‐related mortality. Further evaluation of causality and potential underlying mechanisms is warranted. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Efficacy of Daratumumab Monotherapy on Bone Metabolism of Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results from the Phase 2 Rebuild Study

Efficacy of Daratumumab Monotherapy on Bone Metabolism of Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results from the Phase 2 Rebuild Study

Silence of lncRNA BCAR4 alleviates the deterioration of osteoporosis.

To illustrate the biological function of long non-coding RNA (lncRNA) BCAR4 in triggering osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), thus mediating the progression of osteoporosis. Relative levels of BCAR4 in BMSCs undergoing indicated time points of osteogenic differentiation were examined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). After intervening BCAR4 levels in osteogenically differentiated BMSCs, the relative levels of serum osteocalcin (OCN) and osteopontin (OPN) were detected, as well as ALP activity and mineralization capacity. Female Sprague Dawley (SD) rats were classified into sham group, BMSCs group (administration with BMSCs), RNAi group (administration with BMSCs transfected with si-BCAR4), and control group, with 10 rats per group. Osteoporosis model was generated in the latter three groups by resection of bilateral ovaries. Positive expressions of procollagen type I N propeptide (PINP) and β-C-terminal telopeptide (β-CTx), and β-CTx in rats were determined by enzyme-linked immunosorbent assay (ELISA). Bone density in rat femurs and bone biomechanics were examined using the dual energy X-ray bone densitometer and the three-point bending test, respectively. BCAR4 was downregulated on the 3rd and 7th day of osteogenic differentiation in BMSCs. Overexpression of BCAR4 downregulated OCN and OPN. In the meantime, BCAR4 was able to weaken alkaline phosphatase (ALP) activity and mineralization capacity in BMSCs. The promotive effects of silenced BCAR4 on osteogenic potentials in BMSCs were abolished by overexpression of GLI2. In rats of RNAi group, positive expression of PINP and bone biomechanics were remarkably higher than BMSCs group, whereas they were lower than the sham group. Positive expression of β-CTx was declined in RNAi group compared with that of BMSCs group, and it was still higher than that of sham group. BCAR4 is involved in the osteogenic differentiation of BMSCs. The knockdown of BCAR4 can alleviate the progression of osteoporosis.

Early changes in bone turnover predict longer-term changes in bone mineral density but not trabecular bone score in frail older women.

We sought to examine the association between shorter-term changes in markers of bone turnover and longer-term changes in bone mineral density (BMD) and microstructure in a cohort of frail elderly women with multiple comorbid conditions including osteoporosis. We performed a secondary analysis of a 2-year zoledronic acid trial for osteoporosis in 155 women residents of long-term care communities (mean age 86.9 years). We examined the association of the 6-month change in serum C-terminal crosslinking telopeptide of type I collagen (CTX) and serum intact procollagen type I N propeptide (PINP) with the 12- and 24-month changes in BMD at the spine and hip and the trabecular bone score (TBS), an indirect measure of bone microstructure. For every 0.2-ng/ml 6-month CTX decrease, the corresponding increase in spine BMD at 12 and 24 months was 0.2% (p = 0.7210) and 1.1% (p = 0.0396), respectively; total hip BMD 1.1% (p = 0.0279) and 0.9% (p = 0.0716); and femoral neck BMD 1.7% (p = 0.0079) and 0.9% (p = 0.1698). Similarly, for every 20-ng/ml 6-month PINP decrease, the corresponding increase in spine BMD at 12 and 24 months was 0.9% (p = 0.0286) and 1.4% (p = 0.0012), respectively; total hip BMD 1.4% (p = 0.0005) and 1.4% (p = 0.0006); and femoral neck BMD 2.3% (p < 0.0001) and 2.0% (p < 0.0001). Bone marker changes were not consistently associated with TBS changes. Shorter-term 6-month changes in bone turnover markers are associated with the long-term changes in BMD over 1-2 years in the spine and hip but not with TBS.

Correlation between Bone Turnover Markers and Bone Mineral Density in Patients Undergoing Long-Term Anti-Osteoporosis Treatment: A Systematic Review and Meta-Analysis

This systematic review and meta-analysis aimed to evaluate the correlations between the bone turnover markers (BTMs) and the bone mineral density (BMD) in patients treated for primary osteoporosis and to identify promising BTMs for the prediction of future BMD changes. The PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for relevant studies that investigated the relationship between the BTMs and the BMD changes in patients treated for osteoporosis. All significant correlation coefficients of the baseline BTMs or changes in BTMs from baseline with the BMD changes from baseline under different interventions from eligible studies were used for systematic review and the subgroup analyses. The correlations were analyzed in terms of bone sites, intervention, time duration of BTMs measurements, and time duration of BMD measurements. Twenty-two records reporting correlation coefficients and the corresponding p-values were included, 13 of which were enrolled in the further subgroup analyses. The combined results from the systematic review and meta-analyses indicated that the changes in osteocalcin (OC), procollagen type I N propeptide (PINP), and urine N-terminal crosslinking telopeptide of type I collagen (U-NTX), or the PINP at baseline tended to be useful in evaluating the long-term BMD changes after drug intervention.