High NTX Research Articles

Predictors of clinical outcome in patients with bone metastases from prostate cancer

4555 Background: Bone metastases are a significant cause of morbidity in patients with prostate cancer (PC). To assess the predictive value of bone markers and fractures for clinical outcome in patients with bone metastases from PC, we conducted a retrospective analysis of patients in a large, randomized, controlled trial of zoledronic acid. Methods: Data were analyzed in patients treated with 4 mg zoledronic acid or placebo who had bone marker (n = 411) or fracture (n = 640) information. Cox regression models, adjusted for treatment group, were used to assess the association between bone markers (urinary N-telopeptide [NTX] and bone alkaline phosphatase [BALP]) or fractures (time-dependent variable) and the risk of death or of experiencing a first skeletal-related event (SRE) on study. For bone marker analyses, patients were grouped by low (< 50 nmol/mmol creatinine), moderate (50 to 99), or high (≥ 100) NTX levels and by low (< 146 U/L) or high (≥ 146) BALP. Results: Patients who experienced a fracture on study (19%) had shorter survival compared with patients who did not; the hazard ratio for death was 1.29 (95% CI = 1.01, 1.65; P = .04), suggesting 29% increased risk of death among these patients. When adjusted for previous SRE and baseline ECOG performance status ≥ 2, the risk for death associated with fractures was increased by 23% and trended toward statistical significance (P = .10). Patients with high NTX levels had significantly increased risk of SREs and disease progression (P < .001) compared with patients with low NTX. Relative to low NTX levels, high and moderate NTX levels were associated with a 5.72-fold (95% CI = 4.04, 8.11; P < .001) and 4.10-fold (95% CI = 2.81, 5.97; P < .001) increased risk of death, respectively. High BALP also significantly correlated with an increased risk of a first on-study SRE (P = .028) and bone lesion progression (P < .001). Conclusions: These analyses suggest that pathologic fractures are associated with increased risk if death and that high bone marker levels are associated with increased risk of SREs, bone lesion progression, and shorter survival in patients with PC and bone metastases. The results support appropriate treatment for the prevention of fractures and to decrease bone marker levels. [Table: see text]

Prediction of bone mass gain by bone turnover parameters after parathyroidectomy for primary hyperparathyroidism: neural network software statistical analysis

Primary hyperparathyroidism (pHPT) is the most frequent endocrine hypersecretion disease, and parathyroidectomy is the only curative option, since pharmacologic therapy reduces hypercalcemia but does not impede parathyroid hormone hypersecretion. According to guidelines from the National Institutes of Health, parathyroidectomy is associated with bone mass increase in some asymptomatic patients, while in others bone mass is not changed after surgery. Therefore, we performed the present study in an attempt to elucidate whether a preoperative biochemical bone parameter can be predictive of a significant vertebral bone mass increase in patients with pHPT. For each patient we analyzed the following preoperative parameters: parathyroid hormone, urinary calcium excretion, urinary type I collagen cross-linked N-telopeptide (NTX), osteocalcin, and vertebral computerized bone mineralography. All patients underwent vertebral computerized bone mineralography 12 months after the operation. Statistical analysis was carried out by a neural network program, an event-predicting software modeled on human brain neuronal connections, which is able to examine independent statistical parameters. The patients presenting with high preoperative bone turnover (especially high NTX levels) will have a 5% vertebral bone mass gain in 83.33% of cases after surgery, independently of the National Institutes of Health guidelines. A high preoperative NTX level seems to be the best predictor parameter for postoperative vertebral bone mass gain in patients with pHPT. Our study also illustrates that neural network software may be a valuable method to help elucidate which pHPT patients should undergo surgical treatment.

Urine N-Telopeptide Excretion in Dogs with Appendicular Osteosarcoma

Canine appendicular osteosarcoma (OSA) is a commonly diagnosed cancer that is capable of inducing pathologic bone remodeling. Investigating surrogate indices of bone metabolism may contribute to the diagnostic and therapeutic management of bone malignancies in companion animals. This study evaluated the excretion of N-terminal telopeptide (NTx), a marker of bone resorption that is detected in urine. Sixty-three dogs with appendicular OSA were compared with 29 age-matched healthy dogs. Dogs with appendicular OSA had significantly higher baseline urine NTx excretion than healthy controls (P < .0001). In 17 dogs with OSA treated with either amputation or standardized palliative therapies, significant reductions in urine NTx excretion were observed, suggesting that excessive bone resorption in dogs with OSA may be linked with focal skeletal osteolysis or its consequences. To identify any relationship between indicators of pathologic bone turnover, baseline urine NTx excretion was correlated with serum bone alkaline phosphatase (bALP) or radiographic tumor lengths at diagnosis. No significant correlations were identified between baseline urine NTx excretion and either bALP or tumor length. The findings from this study suggest that high urinary NTx excretion may support the diagnosis of focal skeletal osteolysis in dogs, and reductions in urine NTx excretion after treatment may reflect elimination or minimization of pathologic bone resorption.

The study of bone mineral density and bone turnover markers in postmenopausal women with active rheumatoid arthritis

The aim of this study was to investigate determinants of reduced bone mineral density (BMD) in postmenopausal women with active rheumatoid arthritis (RA) and to evaluate whether there are common markers of bone loss. We evaluated BMD of the femoral neck using dual-energy X-ray absorptiometry, and the measured biochemical markers included serum bone-specific alkaline phosphatase (BALP), serum osteocalcin (OC), and serum cross-linked N-telopeptidases of type I collagen (NTx). Serum BALP and NTx concentrations were measured by enzyme-linked immunsorbent assay, and OC was measured using an immunoradiometric assay. One hundred and forty postmenopausal Japanese women who had not received treatment with bisphosphonates or hormone replacement therapy were entered into the study. Thirty-four patients (41.0%) had femoral osteopenia (T score -1 to -2.5) and 23 patients (27.7%) had osteoporosis (T < -2.5). The body mass index of patients with normal BMD (T score >or= -1.0) was significantly higher (P < 0.01) than in patients with osteoporosis at the femoral neck. The T score exhibited a significant negative correlation with age and the duration of RA disease. Serum BALP and serum OC, markers of osteoblast function, were negatively related to erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and matrix metalloproteinase-3 (MMP-3). However, serum NTx, a marker of resorptive function, exhibited a positive correlation with ESR, CRP, and MMP-3. From these results, this study suggests that generalized bone loss occurs in active RA and is characterized by evidence of bone resorption that is correlated with the high levels of inflammation. Body mass index, disease duration, and high serum NTx level were common risk factors in osteoporosis of postmenopausal women with RA.

The study of bone mineral density and bone turnover markers in postmenopausal women with active rheumatoid arthritis

The aim of this study was to investigate determinants of reduced bone mineral density (BMD) in postmenopausal women with active rheumatoid arthritis (RA) and to evaluate whether there are common markers of bone loss. We evaluated BMD of the femoral neck using dual-energy X-ray absorptiometry, and the measured biochemical markers included serum bone-specific alkaline phosphatase (BALP), serum osteocalcin (OC), and serum cross-linked N-telopeptidases of type I collagen (NTx). Serum BALP and NTx concentrations were measured by enzyme-linked immunsorbent assay, and OC was measured using an immunoradiometric assay. One hundred and forty postmenopausal Japanese women who had not received treatment with bisphosphonates or hormone replacement therapy were entered into the study. Thirty-four patients (41.0%) had femoral osteopenia (T score −1 to −2.5) and 23 patients (27.7%) had osteoporosis (T < −2.5). The body mass index of patients with normal BMD (T score ≥ −1.0) was significantly higher (P < 0.01) than in patients with osteoporosis at the femoral neck. The T score exhibited a significant negative correlation with age and the duration of RA disease. Serum BALP and serum OC, markers of osteoblast function, were negatively related to erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and matrix metalloproteinase-3 (MMP-3). However, serum NTx, a marker of resorptive function, exhibited a positive correlation with ESR, CRP, and MMP-3. From these results, this study suggests that generalized bone loss occurs in active RA and is characterized by evidence of bone resorption that is correlated with the high levels of inflammation. Body mass index, disease duration, and high serum NTx level were common risk factors in osteoporosis of postmenopausal women with RA.

Prognostic Significance of Biochemical Markers of Bone Metabolism in Patients with Bone Lesions from Multiple Myeloma (MM).

BACKGROUND: Biochemical markers of bone metabolism are useful indicators of bone turnover in pts with malignant bone disease. Elevated N-telopeptide (NTX) levels were correlated with increased risks of skeletal-related events (SREs), disease progression, and death in pts with primary bone lesions from MM (Coleman RE, et al. J Clin Oncol. 2005). The prognostic value of other markers (eg, pyridinoline [PYD] and deoxypyridinoline [DXP]) in pts with MM is unknown.METHODS: This study investigated the association between NTX, PYD, DXP, and bone alkaline phosphatase (BAP) levels and risk of SRE or pathologic fracture in pts with MM who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J. 2001). Cut-off values for low, moderate, and high marker levels were based on prior reports and the investigators' experience with bone marker data. Both univariate and multivariate analyses were performed and risk ratios were derived for pts with elevated levels of each bone marker relative to pts with low marker levels.RESULTS: By univariate analysis, moderate (50 to 100 nmol/mmol creatinine) and high (> 100 nmol/mmol creatinine) NTX levels corresponded with significantly increased risks of any SRE, onset of first SRE, or pathologic fracture. Elevated levels of PYD corresponded with a significantly increased risk of SREs, the onset of SREs, and pathologic fracture. Although there were some significant correlations, the association between DXP and BAP levels and risk of skeletal morbidity was inconsistent (Table). In multivariate models, only NTX and DXP were significant, and NTX had a stronger effect.Risk Ratios By Univariate Analysis for SRE Compared With the RespectiveSREPathologic fractureAnyOnset (1st)AnyOnset (1st)NTX ≤ (vs 50 nmol/mmol creatinine)> 50 – 1002.26 (.003)2.76 (.012)2.98 (< .001)3.78 (.001)> 1004.01 (.001)6.80 (< .001)5.35 (< .001)8.87 (< .001)DXP ≤ (vs 15 nmol/mmol creatinine)> 15 – 301.95 (.016)2.14 (.015)2.30 (< .001)2.29 (.009)> 301.89 (.041)3.58 (.006)1.74 (.134)2.88 (.046)PYD ≤ (vs 62 nmol/mmol creatinine)> 621.89 (.009)2.06 (.006)1.74 (.028)1.97 (.017)BAP ≤ (vs 146 U/L)> 1461.48 (.103)1.89 (.042)1.69 (.042)1.86 (.063)CONCLUSIONS: Elevated baseline PYD, DXP, and BAP levels are significant predictors of an increased risk of some SREs and may therefore have clinical value. Elevated NTX levels are a consistent significant predictor of an increased risk of SREs and pathologic fractures. NTX levels may therefore aid in identifying patients at risk for skeletal complications.

High Bone Turnover Markers Predict Poor Outcome in Patients With Bone Metastasis

Bone is a frequent site for metastasis in patients with solid tumors such as breast cancer, prostate cancer, and lung cancer. It may be the first, or even the only, site for metastases in these patients. It is estimated that more than 350,000 patients a year in the United States die with bone metastasis. 1 Bone metastasis is responsible for some of the most devastating complications of malignancy, including pathologic bone fractures, spinal cord compression syndromes, excruciating bone pain, and hypercalcemia. These skeletal metastases can require surgery or radiotherapy to bone, in addition to aggressive analgesic therapy. Furthermore, bone metastases have a major impact on the quality of life and even the survival of these patients. This is clearly illustrated by the authors of the current article, who have reported on patients from the placebo arms of their trials. 2 They found that 143 of 454 patients with bone metastasis from prostate or other solid tumors on the placebo arms of thesetrialsexperiencedpathologicfracturesthroughoutthe 21 months of study. 2 Two hundred forty of these 454 patients required radiotherapy to their bone lesions. The median survival for prostate cancer patients on the placebo arm of the trial was 16.8 months and was only 5.6 months for patients with bone metastasis from other solid tumors. These results demonstrate the extreme toll bone metastasis takes on these patients. Inthisissue,Colemanetalexaminedtheabilityofbone turnover markers to predict negative clinical outcomes in a cohort of almost 2,000 patients with baseline bone metastasisfromprostatecancer,breastcancer,myeloma,orother tumors, who were treated with bisphosphonates. 3 Previous reports of the predictive value of bone turnover markers in these types of patients have been conflicting. However, most of the other studies included much smaller numbers of patients. The overwhelming majority of the patients in the current trial received zoledronate, an extremely potent bisphosphonate. Even patients receiving this very potent bisphosphonate still had progression of their bone disease, experiencing one skeletal-related event per year during the 17 months that they were followed up on. These investigators report on two markers of bone turnover, urinary Ntx (N-telopeptide of collagen type 1) and serum bone-specific alkaline phosphatase (BAP). Ntx is a marker of bone degradation by osteoclasts, and BAP is a marker for bone formation. These markers were chosen because patients with solid tumors and bone metastasis have both increased bone destruction and bone formation. In contrast, patients with myeloma have suppressed bone formation. They found that Ntx levels were better predictors of outcome for these patients than BAP. Patients with hormone refractory prostate cancer had the highest Ntx levels, most likely reflecting the combined effects of increased bone turnover from their metastasis, and bone loss due to low testosterone levels. Furthermore, high levels of Ntx at study entry predicted a poor outcome, and the most recent Ntxlevelwasanevenbetterpredictorforoutcome.Patients with high Ntx levels in their urine had a four- to six-fold increased risk of death and a two-fold increase in the risk of future skeletal events compared with patients with low Ntx levels. Interestingly, once patients were on therapy, Ntx levels did not correlate with tumor burden markers suchasprostate-specificantigeninpatientswithprostate cancer, though it is likely that high Ntx levels reflected increased tumor progression in patients compared with those with low Ntx levels. Furthermore, although Ntx levels reflect bone events, it is reasonable to assume those visceral metastases are also progressing in patients with high Ntx levels. Importantly, high levels of bone resorption markers seem to identify ag roup of patients who are not responding to their current therapy and may need additional antiresorptive therapy as well as changes in their chemotherapy, or may be candidates for trials of novel agents.

Predictive Value of Bone Resorption and Formation Markers in Cancer Patients With Bone Metastases Receiving the Bisphosphonate Zoledronic Acid

Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Clinical Science (42)

Clinical Science (42)

Hormone Replacement Therapy in Postmenopausal Women: Urinary N-Telopeptide of Type I Collagen Monitors Therapeutic Effect and Predicts Response of Bone Mineral Density

PURPOSE: To assess the ability of the urinary N-telopeptide of type I collagen (NTx) to monitor and predict therapeutic effects of hormone replacement therapy (HRT) in postmenopausal women.PATIENTS AND METHODS: To assess the relationship between baseline or change in NTx (predictive variable), and change in lumbar and hip bone mineral density (BMD; outcome variable), we conducted a 2-year randomized controlled study at academic university and private practice medical centers in 236 healthy women 1 to 3 years postmenopausal; 227 women completed the study. Women received estrogen plus progesterone plus calcium (treated group) or calcium alone (control group).RESULTS: In the treated group NTx significantly (P <0.0001) decreased, and spine and hip BMD significantly (P <0.00001 and P <0.005, respectively) increased; in the control group NTx did not change but BMD decreased significantly (P <0.01). Subjects in the highest quartiles for baseline NTx (67 to 188 units) or decreasing NTx (−66% to −87%) through 6 months demonstrated the greatest gain in BMD in response to HRT (P <0.05 and P <0.005). For every increase of 30 units in baseline NTx, the odds of gain in BMD in response to HRT increased by a factor of 5.0 (95% confidence interval [CI] 1.9 to 13.3); for every 30% decrease in NTx through 6 months, the odds of gaining BMD in response to HRT increased by a factor of 2.6 (95% CI 1.6 to 4.4). In the control group an increase of 30 units in mean NTx across the study indicated a higher odds of losing BMD by a factor of 3.2 (95% CI 1.6 to 6.5). A high baseline NTx (>67 units) indicated a 17.3 times higher risk of BMD loss if not treated with HRT.CONCLUSION: These data support the clinical utility of NTx to monitor the antiresorptive effect of HRT in recently postmenopausal women, and to predict changes in BMD in response to HRT.