Higher CTX Levels Research Articles

Zoledronate After Denosumab Discontinuation: Is Repeated Administrations More Effective Than Single Infusion?

After denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impacts on women's health. A sequential therapy with bisphosphonates is recommended, and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study, we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. We measured CTX levels and administered ZOL after 1 month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. Seventy-five percent of patients repeated ZOL infusion. In this group, spine BMD declined significantly (-5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (-0.1 ± 5.5%, P = 0.008). All fractured patients (9.6%) had received >5 Dmab injections and 2 ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 [odds ratio (OR) 2.9, interquartile range (IQR) 1.3-6.6, P = .009] and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, P = .014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss. In patients with uncontrolled CTX levels after Dmab withdrawal, 2 ZOL infusions 6 months apart do not prevent BMD loss and FX.

Bone Turnover Marker Profiling and Fracture Risk in Older Women: Fracture Risk from Age 75 to 90

PurposeA major challenge in osteoporosis is to identify individuals at high fracture risk. We investigated six bone turnover markers (BTMs) to determine association with specific fracture types; the time-frame for risk prediction and whether these are influenced by age at assessment.MethodsPopulation-based OPRA cohort (n = 1044) was assessed at ages 75, 80, 85 and fractures documented for up to 15 years. Six BTMs were analyzed at each time-point (N-terminal propeptide of type I collagen, PINP; total osteocalcin, OC; bone-specific alkaline phosphatase, BALP; C-terminal telopeptide of type I collagen, CTX; tartrate-resistant acid phosphatase 5b, TRAcP5b; urinary osteocalcin). Hazard ratios (HR) for any, major osteoporotic, vertebral and hip fractures were calculated as short (1, 2, 3 years) and long-term risk (5, 10, 15 years).ResultsAt 75 year, high CTX levels were associated with an increased risk of all fractures, including major osteoporotic fractures, across most time-frames (HRs ranging: 1.28 to 2.28). PINP was not consistently associated. Urinary osteocalcin was consistently associated with elevated short-term risk (HRs ranging: 1.83–2.72). Other BTMs were directionally in accordance, though not all statistically significant. BTMs were not predictive for hip fractures. Association of all BTMs attenuated over time; at 80 year none were associated with an increased fracture risk.ConclusionCTX, urinary OC and TRAcP5b are predictive for fracture in a 1 to 3 year, perspective, whereas in the long-term or above age 80 years, BTMs appear less valuable. Resorption markers, particularly CTX, were more consistently associated with fracture risk than formation markers in the very elderly.

Serum levels of C-Terminal Telopeptide (CTX) are Associated with Muscle Function in Community-Dwelling Older Adults.

Markers of bone metabolism have been associated with muscle mass and function. Whether serum cross-linked C-terminal telopeptides of type I collagen (CTX) is also associated with these measures in older adults remains unknown. In community-dwelling older adults at high risk of falls and fractures, serum CTX (biochemical immunoassays) was used as the exposure, while appendicular lean mass (dual-energy x-ray absorptiometry) and muscle function (grip strength [hydraulic dynamometer], short physical performance battery [SPPB], gait speed, sit-to-stand, balance, Timed Up and Go [TUG]) were used as outcomes. Potential covariates including demographic, lifestyle, and clinical factors were considered in statistical models. Areas under the receiver operating characteristic (ROC) curves were calculated for significant outcomes. Two hundred and ninety-nine older adults (median age: 79 years, interquartile range: 73, 84; 75.6% women) were included. In multivariable models, CTX was negatively associated with SPPB (β = 0.95, 95% confidence interval [CI]: 0.92, 0.98) and balance (β = 0.92, 0.86, 0.99) scores, and positively associated with sit-to-stand (β = 1.02, 95% CI: 1.00, 1.05) and TUG (β = 1.03, 95% CI: 1.00, 1.05). Trend line for gait speed (β = 0.99, 95% CI: 0.98, 1.01) was in the hypothesized direction but did not reach significance. Area under the ROC curves showed low diagnostic power (<0.7) of CTX in identifying poor muscle function (SPPB: 0.63; sit-to-stand: 0.64; TUG: 0.61). In older adults, higher CTX levels were associated with poorer lower-limb muscle function (but showed poor diagnostic power for these measures). These clinical data build on the biomedical link between bone and muscle.

Connection between bone remodeling and inflammatory markers in obstructive sleep apnea in relation to disease severity: a preliminary study

INTRODUCTION There is growing evidence that obstructive sleep apnea (OSA) influences both bone metabolism and structure. Chitinase‑3‑like protein 1 (YKL‑40) is a novel inflammatory and remodeling marker, the levels of which were shown to increase in OSA. YKL‑40 can probably alter the bone turnover. OBJECTIVES The aim of the study was to assess a possible interplay between YKL‑40 and bone turnover markers in patients with different stages of OSA, and to evaluate the relation between bone mass, severity of OSA, and YKL‑40 levels. PATIENTS AND METHODS The study involved 72 male patients with OSA. They were divided into 3 groups according to disease severity, using the apnea-hypopnea index (AHI): group 1 (n = 18; 5≤ AHI <15), group 2 (n = 25; 15≤ AHI <30), and group 3 (n = 29; AHI ≥30). All patients underwent polysomnography and densitometry. Fasting blood samples were collected for YKL‑40, C‑terminal telopeptide of typeI collagen (CTX), procollagen type 1 N‑terminal propeptide (P1NP), and other markers. RESULTS P1NP differed between groups 1 and 2, as well as groups 1 and 3 (P = 0.02). Group 2 had higher CTX levels than group 1 (borderline significance, P = 0.05). A simple linear regression analysis showed that serum YKL‑40 levels were associated with the levels of CTX (P <0.0001, β = 0.9871) and P1NP (P <0.0001, β = 0.9780). CONCLUSIONS Our study might suggest that YKL‑40 is associated with bone turnover in OSA. We may assume that this marker influences both bone formation and destruction; thus, OSA could be characterized by preserved bone mineral density.

Elevated Bone Turnover Markers are Associated with Distal Radius Fractures in Pre-menopausal Women: Level 3 Evidence

Grant received from: OREF Resident Research Project Grant There is no financial information to disclose. Vitamin D deficiency and increased bone turnover markers (BTM) are associated with an increased risk of fragility fractures. We hypothesized that young patients with distal radius fractures (DRF) would have lower levels of 25-hydroxyvitamin D (25(OH)D) and increased levels of serum BTMs compared to controls without fracture. Premenopausal women with DRF (n = 20) were prospectively enrolled and compared to age-matched individuals without a fracture (n = 20). Outcome measures included serum levels of 25(OH)D, parathyroid hormone (PTH), markers of bone formation (osteocalcin [OC], N-terminal extension propeptide of type I collagen [P1NP], and bone-specific alkaline phosphatase [BSAP], and markers of bone resorption (C-terminal telopeptide of type-I collagen [CTX-1]). Associations between BTM and DRF were assessed with conditional logistic regression and the utility of markers for fracture prediction was assessed with a receiver operator characteristic (ROC) analysis. The fracture group and control group were comparable in terms of age, body mass index, and age at menarche. Fracture patients had higher levels of OC (23.09 ± 6.86 versus 17.23 ± 8.19 ng/mL, mean difference = 6.01 ng/mL, 95%CI = 1.32 - 10.70) and P1NP (72.15 ± 25.80 versus 51.99 ± 24.18 ng/mL, mean difference = 20.44 ng/mL, 95% CI = 4.53 - 36.34) and trended toward higher levels of CTX (0.43 ± 0.21 versus 0.32 ± 0.21 ng/mL, mean difference = 0.10, 95% CI = -0.01 - 0.22). The levels of 25(OH)D, PTH, and BSAP were similar between groups. Conditional logistic regression revealed independent associations between DRF and CTX (OR = 7.4 per SD increase, 95% CI = 1.3 - 43.6, P = 0.026), and OC (OR = 2.4 per SD increase, 95% CI = 1.0 - 5.8, P = 0.043). Associations between DRF and P1NP (OR = 4.78 per SD increase, 95% CI = 0.97 - 23.66, P = 0.055) and BSAP (OR = 3.16 per SD increase, 95% CI = 0.96 - 10.37, P = 0.058) trended towards significance (Table 1). Serum 25(OH)D and PTH were not associated with DRF. ROC analyses demonstrated moderate performance for OC, P1NP, BSAP and CTX in predicting DRF (Figure 1). •25(OH)D levels were not associated with DRF in pre-menopausal women.•Patients with DRF had increased levels of BTMs of formation and resorption.•Women with increased levels of OC and CTX were at higher risk of fracture.•BTMs may be helpful in predicting fractures in pre-menopausal women.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

La prueba CTX como evaluador de riesgo en el diagnóstico y tratamiento de osteonecrosis de los maxilares inducida por el uso de bifosfonatos

A literature review was conducted to determine the effectiveness of the C-terminal crosslinking telopeptide (CTX) serologic test, which has been suggested to predict the risk of developing osteonecrosis of the jaw in patients taking oral bisphosphonates. Osteonecrosis of the jaw (ONJ) is a condition that causes avascular necrosis of the alveolar bone, which occurs in patients treated with bisphosphonates. It has been suggested that a CTX value below 100 pg/ml represents a high risk for ONJ , while between 100 and 150 pg / ml a moderate risk and above 150pg/ml minimal risk. The CTX test has been controversial and it has not been possible to frame it as strong evidence, since several studies have found variable results. Patients with very low CTX levels have not developed ONJ, and others with very high CTX levels, supposedly safe, have done . CTX test is a useful test to inform the dentist about the activity level on patient ́s bone turnover, and may be useful to advise the patient. Low CTX levels could serve to delay a surgical procedure that is not deemed urgent.

Microstructural alterations of trabecular and cortical bone in long-term HIV-infected elderly men on successful antiretroviral therapy.

Progress in antiretroviral therapy (ART) has resulted in an almost normal life expectancy for HIV-infected individuals, but an increased risk of fragility fractures has been identified. We investigated the influence of long-term HIV infection on successful ART on bone microstructure in elderly men. A cross-sectional, case–control study. Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) were performed in 28 HIV-positive men between 60 and 70 years old on successful ART. Controls were 112 HIV-negative men matched for age 4 years and BMI (4 kg/ m²). HIV-positive men (median CD4þ cell count, 589 cells/ml; BMI, 24.8 kg/m²) had a median duration of HIV infection of 18.2 years. Compared with HIV-negative men, they had a lower DXA-measured areal bone mineral density at total hip (3.2%, P¼0.050) and ultra-distal radius (8.4%, P¼0.001). At distal radius and tibia, we observed microstructural alterations with a lower total density (16%, P¼ 0.005 and 14.3%, P¼ 0.039), trabecular density (11.6%, P¼ 0.012 and 12.2%, P¼ 0.007) and cortical area (17.5%, P¼ 0.002 and 12.2%, P¼ 0.01). In addition, they had a lower trabecular number (P¼ 0.036), higher trabecular spacing (P¼ 0.027) and lower cortical thickness (19.9%; P¼ 0.008) at distal radius. beta-crosslaps (CTX) and vitamin D levels were higher than in controls. By multivariate analyses, HIV status, higher CTX levels, lower physical activity and estradiol levels were determinants of bone density and microstructure alterations. HIV-infected elderly men on successful ART have trabecular and cortical bone microstructure alterations associated with higher bone resorption, despite adequate vitamin D supplementation.

FRI0292 Correlation biomarkers of cartilage and bone turnover with disease activity, ASDAS, function, quality of life, radiology and magnetic resonance imaging in patients with early spondiloarthritis

ObjectivesTo determine the relationship between biomarkers and activity, functional capacity, quality of life and radiology in early SpA.To analyse the influence of sex, HLA B27, psoriasis, osteitis in MRI and...

High C-Terminal Cross-Linking Telopeptide of Collagen Type-I (CTX) Predicts for Poor Overall Survival in Patients with Multiple Myeloma Who Receive Frontline Therapy with Immunomodulatory Drugs (IMiDs) but Not with Bortezomib-Based Regimens

Abstract 935Lytic bone disease is a frequent complication of multiple myeloma (MM). Biochemical markers of bone metabolism provide information on bone dynamics and reflect activity in the bones. Several studies show that different bone markers are altered in myeloma patients, reflect the extent of bone disease and correlate with survival in the conventional chemotherapy era. Nevertheless, there is almost no information about their impact on the survival of myeloma patients who are treated upfront with novel agents.To address this issue we studied 122 consecutive, unselected, newly diagnosed patients with symptomatic MM (66M/56F, median age 71 years, range 36–88 years) who were diagnosed and treated in a single center (University of Athens, Greece). All patients received upfront novel agents: 75 patients IMiDs-based and 47 patients bortezomib-based regimens. The following bone remodeling markers were evaluated in the patients’ serum before the administration of any kind of therapy: i) osteoclast regulators: sRANKL and osteoprotegerin (OPG); ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption markers: CTX and TRACP-5b; and iv) bone formation markers: bone-specific alkaline phosphatase (bALP) and osteocalcin. The above molecules were also measured in 36 gender- and age-matched, healthy controls. Evidence of bone involvement was documented using plain radiographs and MRI of the spine in all patients.Twenty-five (20%) patients had ISS-I disease, while 46 (37%) patients had ISS-II and 51 (41%) stage ISS-III disease. Fifty-eight (47%) patients had Hb<10 g/dl and 24 (19%) patients had serum creatinine >2 mg/dl. The presence of lytic bone disease was documented in 76% of the patients. MRI evaluation of the spine revealed that 41% of the patients had focal, 38% diffuse, 19% normal, and 2% a variegated pattern of marrow involvement. At diagnosis, MM patients had increased serum concentrations of sRANKL (mean±SD: 0.4±0.5 pmol/L vs. 0.1±0.2 pmol/L; p<0.001), OPG (6.4±3.3 pmol/L vs. 4.2±1.7 pmol/L; p<0.001), CTX (0.90±0.97 ng/ml vs. 0.3±0.2 ng/ml; p<0.001),TRACP-5b (2.7±2 U/L vs. 1.6±0.7 U/L; p<0.001), Dkk-1 (59.4±38.7 ng/ml vs. 32.8±13 ng/ml; p<0.001) and sRANKL/OPG ratio (0.08±0.13 vs. 0.04±0.05; p=0.003) and decreased levels of bALP (21.6±15.1 U/L vs. 29.4±7.8 U/L; p=0.003) compared to controls, while their levels correlated with the extend of bone disease. Patients with diffuse pattern had higher CTX concentrations compared to all other others (0.95±1.2 ng/ml vs. 0.6±0.51 ng/ml; p=0.04). The median survival of all patients was 59 months. In the univariate analysis, among the studied bone markers, only CTX, as a continuous variable, was predictive of survival (HR: 1.292, p=0.024). Patients with low CTX concentrations (<0.28 ng/ml; lower quartile; N=29) had superior survival compared to patients with higher CTX concentrations (not reached vs. 54 months respectively; p=0.034). This was more profound in patients treated with IMiDs-based regimens: the median survival of those with low CTX levels (<0.28 ng/ml) has not been reached yet vs. 39 months of all others (p=0.02; Figure). There was no difference regarding the effect of CTX on survival between patients who received upfront thalidomide- or lenalidomide-based regimens. On the contrary, in patients who were treated with bortezomib-based schemes, high CTX could not define a poor prognosis group of patients. In patients with normal or focal MRI pattern of bone marrow involvement, low CTX concentrations also correlated with superior survival compared to all other patients (not reached vs. 54 months respectively; p=0.04). Serum LDH (as dichotomous variable >225 U/L; p=0.011, and as continuous variable; p=0.019), ISS stage (p=0.02) and anemia (Hb<10 g/dl; p=0.01) were also associated with survival in the univariate analysis. The presence of osteolytic disease at diagnosis had no impact on survival. In the multivariate analysis only ISS (p=0.02) and LDH (>225 U/L; p=0.038) were predictive for survival.Our study suggests that in the era of novel agents, only CTX, among 7 serum bone remodeling markers, correlated with survival. In particular, high CTX levels can distinguish a subset of patients who receive frontline IMiDs-based therapies and who have poor prognosis. This was not observed with bortezomib-based therapies, possibly due to the beneficial effect of bortezomib on bone metabolism. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Opportunistic Screening for Osteoporosis During Abdominal CT Scanning: Recipient of Young Investigator Award

To examine the association between oestradiol (E2), testosterone (T), SHBG levels and vertebral fractures' (VFs) prevalence in asymptomatic men.The study cohort consists of a population of 112 consecutive men (mean ± SD (range) age, weight and BMI were 62.9 ± 9.2 (41–84) years, 75.0 ± 13.8 (45–120) kgs and 26.4 ± 4.7 (18.0–39.6) kg/m2, respectively). Lateral vertebral fracture assessment (VFA) images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative approach and morphometry. Serum levels of T, E2, CTx and osteocalcine were measured. Free androgen index (FAI) and free estradiol index (FEI) were calculated respectively from the ratio of serum T and E2 to SHBG.Among the 112 men, 38 (33.9%) had densitometric osteoporosis, and on VFA, VFs were identified in 60 (53.5%): 24 men had grade 1 and 36 had grade 2 or 3 VFs (32.1%). Men with VFs weighted less and had a statistically significant lower lumbar spine and total hip BMD and T-scores than those without a VFA-identified vertebral fracture. Levels of osteocalcine, CTx, and SHBG were statistically higher in men with grades 2 and 3 VFs than men with grade 1 VFs and those without VFs whereas FAI and FEI levels were significantly lower. Comparison of patients according to quartiles of SHBG levels showed that men in the highest quartile were older, had a lower lumbar spine and total hip BMD and a higher prevalence of osteoporosis and VFs. They had also higher levels of CTx. Stepwise regression analysis showed that the osteoporotic status and SHBG was independently associated to the presence of VFs.Men with asymptomatic densitometric VFs have lower BMD than subjects without VFs. They have evidence of higher SHBG levels and hence lower free sex steroids as well as increased bone resorption. This study confirms that BMD and CTx are the most important determinant of asymptomatic VFs, and that SHBG is an independent risk factor that must be taken into account.

The Change of Bone Metabolism in Ovariectomized Rats : Analyses of MicroCT Scan and Biochemical Markers of Bone Turnover

ObjectiveThe purpose of this study was to verify the appropriateness of ovariectomized rats as the osteoporosis animal model.MethodsTwelve female Sprague-Dawley rats underwent a sham operation (the sham group) or bilateral ovariectomy [the ovariectomy (OVX) group]. Eight weeks after operations, serum biochemical markers of bone turnover were analyzed; osteocalcin and alkaline phosphatase, which are sensitive biochemical markers of bone formation, and C-terminal telopeptide fragment of type I collagen C-terminus (CTX), which is a sensitive biochemical marker of bone resorption. Bone histomorphometric parameters and microarchitectural properties of 4th lumbar vertebrae were determined by micro-computed tomographic (CT) scan.ResultsThe OVX group showed on average 75.4% higher osteocalcin and 72.5% higher CTX levels than the sham group, indicating increased bone turnover. Micro-CT analysis showed significantly lower bone mineral density (BMD) (p=0.005) and cortical BMD (p=0.021) in the OVX group. Furthermore, the OVX group was found to have a significantly lower trabecular bone volume fraction (p=0.002).ConclusionOur results showed that bone turnover was significantly increased and bone mass was significantly decreased 8 weeks after ovariectomy in rats. Thus, we propose that the ovariectomized rat model be considered a reproducible and reliable model of osteoporosis.

The relationship between sex steroids, bone turnover and vertebral fracture prevalence in asymptomatic men

To examine the association between oestradiol (E2), testosterone (T), SHBG levels and vertebral fractures' (VFs) prevalence in asymptomatic men. The study cohort consists of a population of 112 consecutive men (mean±SD (range) age, weight and BMI were 62.9±9.2 (41-84) years, 75.0±13.8 (45-120) kgs and 26.4±4.7 (18.0-39.6) kg/m(2), respectively). Lateral vertebral fracture assessment (VFA) images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative approach and morphometry. Serum levels of T, E2, CTx and osteocalcine were measured. Free androgen index (FAI) and free estradiol index (FEI) were calculated respectively from the ratio of serum T and E2 to SHBG. Among the 112 men, 38 (33.9%) had densitometric osteoporosis, and on VFA, VFs were identified in 60 (53.5%): 24 men had grade 1 and 36 had grade 2 or 3 VFs (32.1%). Men with VFs weighted less and had a statistically significant lower lumbar spine and total hip BMD and T-scores than those without a VFA-identified vertebral fracture. Levels of osteocalcine, CTx, and SHBG were statistically higher in men with grades 2 and 3 VFs than men with grade 1 VFs and those without VFs whereas FAI and FEI levels were significantly lower. Comparison of patients according to quartiles of SHBG levels showed that men in the highest quartile were older, had a lower lumbar spine and total hip BMD and a higher prevalence of osteoporosis and VFs. They had also higher levels of CTx. Stepwise regression analysis showed that the osteoporotic status and SHBG was independently associated to the presence of VFs. Men with asymptomatic densitometric VFs have lower BMD than subjects without VFs. They have evidence of higher SHBG levels and hence lower free sex steroids as well as increased bone resorption. This study confirms that BMD and CTx are the most important determinant of asymptomatic VFs, and that SHBG is an independent risk factor that must be taken into account.

The Peroxisome Proliferator-Activated Receptor-γ Agonist Rosiglitazone Increases Bone Resorption in Women with Type 2 Diabetes: A Randomized, Controlled Trial

In previous studies, with up to 16 weeks of exposure to rosiglitazone or pioglitazone, circulating markers of bone formation [procollagen I N-terminal propeptide (P1NP), osteocalcin, and bone-specific alkaline phosphatase] decreased but no change in bone resorption markers was found. We examined the effect of rosiglitazone on bone resorption and formation markers when used for 24 weeks. This post-hoc analysis of a double-blind, placebo-controlled, randomized trial evaluated the effects of 6 months of rosiglitazone use versus placebo on circulating markers of bone turnover in 111 patients with type 2 diabetes and cardiovascular disease or additional cardiac risk factors. The principal end points for analysis were changes in bone formation and resorption markers, measured by P1NP and carboxy-terminal cross-links (CTX), respectively. There were 111 subjects who completed the study and had baseline and 6-month data; mean age was 56, including 41% women and 67% nonwhite (50 black, 18 Hispanic, and six other), and subjects were evenly distributed between placebo and rosiglitazone groups. Women treated with rosiglitazone had higher CTX levels (0.43 ng/mL) than those who received placebo (0.23 ng/mL) (P = 0.007), with no significant differences in P1NP or OPG. Overall, in stratified analyses of men and in stratified analyses among different ethnicities, there were no statistically significant differences observed in CTX, P1NP, OPG, PTH, or 25-OHD between the treatment groups. Women taking rosiglitazone had higher circulating markers of bone resorption, which is contrary to prior studies of shorter duration, where the principal observation was a decrease in markers of bone formation.