High NTX Research Articles

Baseline N-Telopeptide Levels Correlate with Risk of Skeletal Morbidity in Patients with Multiple Myeloma during Zoledronic Acid Therapy.

BACKGROUND: Biochemical markers of bone metabolism provide valuable information about rates of bone turnover in patients with malignant bone disease. N-telopeptide of type I collagen (NTX) is released during osteolysis and is indicative of pathologic increases in bone resorption. Elevated NTX levels recently have been correlated with increased risks of skeletal-related events (SREs, defined as pathologic fracture, surgery to bone, spinal cord compression, hypercalcemia of malignancy, and the requirement for palliative radiotherapy), disease progression, and death in patients with bone metastases from solid tumors (Coleman RE, et al. J Clin Oncol. 2005; 23:4925–4935; Brown J, et al. J Natl Cancer Inst . 2005; 97:59–69).METHODS: The current univariate analysis investigated the correlation between NTX levels at baseline and SREs (including palliative radiotherapy to bone) in patients with multiple myeloma who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J. 2001; 7:377–387).RESULTS: Forty-three patients had low NTX (< 50 nmol/mmol creatinine), 45 had moderate NTX (50 to < 100 nmol/mmol creatinine), and 18 had high NTX (≥ 100 nmol/mmol creatinine) at baseline. Patients with either moderate or high NTX at baseline had significantly increased risks of on-study SREs and significantly increased risks of experiencing their first SRE while on-study compared with patients with low NTX (Table). A similar correlation was also observed for pathologic fractures alone. The risk of first events was especially high in the high NTX group. There were no significant correlations between NTX levels and the requirement for palliative radiotherapy alone.Hazard Ratios for Time to Onset and Occurrence of On-Study SRE Compared With Low (< 50 nmol/mmol creatinine) NTX (P Value)SREPathologic fracturePalliative radiotherapyBaseline NTX levelOnset of first SREAny eventOnset of first eventAny eventOnset of first eventAny eventModerate*2.76 (.012)2.26 (.003)3.78 (.001)2.98 (< .001)1.21 (.777)1.61 (.386)High†6.80 (< .001)4.01 (.001)8.87 (< .001)5.35 (< .001)3.23 (.095)3.44 (.124)*50 to < 100 nmol/mmol creatinine.; † ≥ 100 nmol/mmol creatinine.Conclusions: Multiple myeloma patients with elevated baseline NTX levels have a significantly increased risk of experiencing SREs.

Bone metabolism subgroups identified as hip fracture patients via clustering.

The aim of the study was to describe the bone metabolism status that underlies a hip fracture. Estimated glomerular filtration rate (e-GFR), calcium (Ca), phosphorus (P), total (ALP) and bone specific alkaline phosphatase (b-ALP), intact parathyroid hormone (i-PTH), 25-hydroxy-vitamin D (25OHD), total procollagen type I amino-terminal propeptide (PINP), and N-terminal peptide of collagen I (NTx), measured at admission in 272 hip fracture patients, were ex post analyzed by K-means clustering and principal component analysis and were evaluated by a clinician. Four components, mainly consisting of b-ALP, PINP, ALP, and NTx; e-GFR and P; i-PTH and 25OHD; and Ca explained about 70% of the variability. A total of 184 patients clustered around a centroid (A) with low 25OHD (13.2 ng/ml), well-preserved kidney function (e-GFR=67.19 ml/min/1.73m2), normal Ca, P, i-PTH and bone markers, with the exception of slightly increased NTx (24.82nMBCE). Cluster B (n=70) had increased i-PTH (93.38 pg/ml), moderately decreased e-GFR, very low 25OHD (8.68 ng/dl), and high bone turnover (b-ALP 28.46 U/L, PINP 69.87 ng/ml, NTx 31.3nMBCE). Cluster C (n=17) also had hyperparathyroidism (80.35 pg/ml) and hypovitaminosis D (9.15 ng/ml), low e-GFR(48.89 ml/min/1.73m2), and notably high ALP(173 U/L) and bone markers (b-ALP 44.64 U/L, PINP 186.98 ng/ml,NTx 38.28nMBCE). According to the clinician, 62 cases clearly had secondary hyperparathyroidism. Based on serum measurements, the dominant patterns of bone metabolism were normal bone turnover with high normal NTx, and secondary hyperparathyroidism related to chronic kidney disease and hypovitaminosis D. The bone formation markers, e-GFR, NTx, and P composed the most important factors.

Gender-Specific Impact of Cadmium Exposure on Bone Metabolism in Older People Living in a Cadmium-Polluted Area in Thailand.

To elucidate the influence of cadmium exposure on bone metabolism, associations between urinary/blood cadmium and bone resorption/formation markers were investigated in older cadmium exposed men and women. Increased urinary cross-linked N-telopeptide of type I collagen (NTx), a bone resorption marker, was found to be associated with increased levels of parathyroid hormone, fractional excretion of calcium, and urinary/blood cadmium after adjusting for confounding factors in men. In women, urinary NTx was significantly associated with only urinary cadmium and a strong relationship with increased fractional excretion of calcium. Risk for bone metabolic disorders, indicated by high urinary NTx, significantly increased in men with blood cadmium ≥ 10 μg/L or urinary cadmium ≥ 10 μg/g creatinine. Increased osteocalcin level was significantly associated with increased blood cadmium in men. In conclusion, cadmium exposure appeared to have an influence on bone remodeling both bone resorption and formation in this population of older Thai men, and blood cadmium was more closely associated with bone metabolism than urinary cadmium.

The effect of LLLT on bone metabolism in children with severe cerebral palsy (a secondary publication).

It is said that the average frequency of bone fracture in hospitalized children with severe cerebral palsy (unable to remain seated) is 1% (0.2 to 2.0%). Cerebral palsy patients' bones are known to be vulnerable to fracture, and refractory bone atrophy may be observed. However, the effect of low level laser therapy (LLLT) on bone density or bone metabolism has not been fully investigated. In recent years, tests for bone density or bone metabolism markers have become available. In this study, we evaluated changes in bone density and bone metabolism markers in 4 children with severe cerebral palsy who underwent LLLT for an average of 22 days. B-ALP, a marker of ossification, increased 1 month after the start of irradiation in 3 of the 4 subjects and returned to a level close to the pre-irradiation level 2 months after the start of irradiation. In the remaining subjects in whom B-ALP failed to increase, B-ALP had been low before irradiation. Urinary N-terminal telopeptide (NTx) levels, a marker of bone resorption, decreased in 3 of the 4 subjects after the start of irradiation and remained low even 10 months later. Serum NTx levels tended to decrease in 3 of the 4 subjects. The levels of serum NTx/Crea, Deoxy-Pyridinoline (DPd) and DPd/Crea (DPd/Crea) also decreased in 3 of the 4 subjects. Transient decreases in intact parathyroid hormone (PTH) levels were observed in all 4 cases. Changes were particularly apparent in 2 cases: one with high NTx levels, which showed enhanced bone resorption, and one with high PTH levels, probably due to a vitamin D (VitD) deficiency. Although the metacarpal bone density measured by DIP was found to be lower than in normal children, there were no changes due to LLLT. These results suggest that LLLT has a positive influence on bone metabolism in that it temporarily increases bone formation and suppresses bone resorption while also tending to improve secondary hyperparathyroidism caused by VitD deficiency. Enhanced bone resorption in the case with high NTx levels was noteworthy, together with marked changes in the case with high PTH levels due to VitD deficiency. These positive influences on bone metabolism merit attention as potential new indications of LLLT.

P3-024 - The Clinical Significance of the Serum Cross-Linked N-Telopeptide of Type I Collagen as a Prognostic Marker for Non-Small-Cell Lung Cancer

The clinical significance of the serum crosslinked N-telopeptide of type I collagen (NTx) as a prognostic marker for non-small-cell lung cancer (NSCLC) was evaluated. We have revealed that a high serum NTx level (>22 nmol bone collagen equivalents (BCE)/L) appears to be a risk factor for a reduction in overall survival in patients with NSCLC. Introduction: Lung cancer is the leading cause of cancer-related death. Many patients with lung cancer are in its advanced stages at the time of diagnosis. The 5-year survival rate for lung cancer is 10% to 20%, and the prognosis for patients with lung cancer is still poor. The crosslinked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of bone matrix. Patients and Methods: We measured serum NTx levels in patients who underwent staging during hospitalization for the initial treatment of lung cancer in our department. We examined whether serum NTx levels would be relevant to the prognosis of non-small-cell lung cancer (NSCLC). Results: This study included 176 patients with lung cancer (125 men and 51 women), including 109 with adenocarcinoma, 53 with squamous cell carcinoma, 6 with large-cell carcinoma, and 8 with other cancer types. Univariate and multivariate analysis using the Cox proportional hazards model revealed a particularly close associ- ation between sex, performance status, disease stage, and serum NTx levels and overall survival (OS). A median OS of 368 days was observed for patients with a serum NTx level 22 nmol BCE/L, which was significantly longer than the 197 days for patients with a serum NTx level 22 nmol BCE/L (hazard ratio (HR), 2.02; 95% confidence interval (CI), 1.36-2.99; log-rank P.00037). Conclusions: We have revealed that a high serum NTx level ( 22 nmol BCE/L) appears to be a risk factor for a reduction in OS in patients with NSCLC.

Kidney transplantation restored uncoupled bone turnover in end-stage renal disease

While kidney transplantation (KTx) reverses many disorders associated with end-stage renal disease (ESRD), patients who have received KTx often have chronic kidney disease and bone and mineral disorder (CKD-MBD). However, it is unknown how bone metabolism changes by KTx. Living donor-KTx recipients (n = 34) at Tokyo Women's Medical University were prospectively recruited and the levels of bone-specific alkaline phosphatase (BAP) and serum cross-linked N-telopeptides of Type 1 collagen (NTX) were measured before, 6 and 12 months after transplantation. Before KTx, serum BAP was within the reference range in more than half of patients while NTX was high in most patients. Serum NTX was higher in patients with longer dialysis durations compared to that with shorter durations before KTx. However, there was no difference in serum BAP between these patients. After KTx, BAP increased while NTX decreased along with the decline of PTH. In addition, the numbers of patients who showed high BAP and NTX were comparable after KTx. These results suggest that bone formation is suppressed and uncoupled with bone resorption in patients with ESRD and this uncoupling is restored by KTx. Further studies are necessary to clarify the mechanism of bone uncoupling in patients with ESRD.

Clinical Significance of the Serum Crosslinked N-Telopeptide of Type I Collagen as a Prognostic Marker for Non–Small-Cell Lung Cancer

IntroductionLung cancer is the leading cause of cancer-related death. Many patients with lung cancer are in its advanced stages at the time of diagnosis. The 5-year survival rate for lung cancer is 10% to 20%, and the prognosis for patients with lung cancer is still poor. The crosslinked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of bone matrix. Patients and MethodsWe measured serum NTx levels in patients who underwent staging during hospitalization for the initial treatment of lung cancer in our department. We examined whether serum NTx levels would be relevant to the prognosis of non–small-cell lung cancer (NSCLC). ResultsThis study included 176 patients with lung cancer (125 men and 51 women), including 109 with adenocarcinoma, 53 with squamous cell carcinoma, 6 with large-cell carcinoma, and 8 with other cancer types. Univariate and multivariate analysis using the Cox proportional hazards model revealed a particularly close association between sex, performance status, disease stage, and serum NTx levels and overall survival (OS). A median OS of 368 days was observed for patients with a serum NTx level < 22 nmol BCE/L, which was significantly longer than the 197 days for patients with a serum NTx level ≥ 22 nmol BCE/L (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.36-2.99; log-rank P = .00037). ConclusionsWe have revealed that a high serum NTx level (> 22 nmol BCE/L) appears to be a risk factor for a reduction in OS in patients with NSCLC.

N-telopeptide of type I collagen is useful for monitoring therapeutic response in non-small cell lung cancer patients with bone metastases

Elevated levels of N-telopeptide of type I collagen (NTX) are associated with skeletal-related events and death. However, it is unclear whether NTX is useful for monitoring therapeutic response in non-small cell lung cancer (NSCLC) patients with bone metastases. Urinary NTX levels were assessed at baseline and after one cycle of chemotherapy in 30 NSCLC patients with bone metastases. NTX levels were categorized as normal (NTX <64nmol/mmol creatinine) or high (NTX ≥64nmol/mmol creatinine). In 30 patients, the median NTX level at 1month was significantly lower than that at baseline (P=0.0016). The NTX levels after treatment were significantly lower than those at baseline in 20 patients with partial response (n=2) or stable disease (n=18). However, no significant difference of the NTX levels was observed in 10 patients with progressive disease. Sixteen (53.3%) of 30 patients had high baseline NTX levels. Ten patients had normal NTX levels after one cycle of chemotherapy, whereas 6 patients also had high NTX levels after treatment. The 10 patients with normal NTX levels had significantly better prognosis than the 6 patients with high NTX levels. Urinary NTX levels at 1month after chemotherapy may be useful for predicting therapeutic response in NSCLC patients with bone metastases. Normalization of elevated baseline NTX at 1month after chemotherapy was associated with survival benefits.

Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease

Skeletal-related events (SREs) are common in patients with osteolytic lesions from multiple myeloma (MM), and result in substantial morbidity. We report herein a comprehensive, retrospective, multivariate analysis of prognostic factors for survival and first on-study SRE in MM patients using data from the phase III, randomized study comparing zoledronic acid with pamidronate in MM or breast cancer. Cox regression analyses were used to assess 22 variables for prognostic significance (defined as associations with P<0.05) in patients with bone metabolism marker assessments and complete baseline variable data. Of 510 evaluable MM patients, 282 had complete covariate information and were included in models. Reduced Cox multivariate models identified five significant prognostic factors for first SRE (weight, race, high N-terminal cross-linked telopeptide of type I collagen (NTX), high pain score, and need for narcotic analgesics) and seven for survival (age, SRE history, myeloma subtype, anemia, high lactate dehydrogenase, high NTX, and low albumin levels). High NTX was the only variable associated with elevated risks of both first SRE and death (P< or =0.02 for each). These analyses identified prognostic factors for SREs and survival in patients with MM. Taken together with current staging systems, these factors could further facilitate decision making for optimal treatment of myeloma bone disease, although further prospective assessments are needed.

A345 High Baseline NTX Predicts for Inferior Survival and Shorter Time to First SRE in Multiple Myeloma

A345 High Baseline NTX Predicts for Inferior Survival and Shorter Time to First SRE in Multiple Myeloma

POD-3.05: N-telopeptide of Type I Collagen (NTX) Response to Zoledronic Acid in Patients with Bone Metastases from Prostate Cancer

Zoledronic acid (ZOL) significantly delays the onset of skeletal-related events and reduces patients' ongoing risk of skeletal morbidity. Moreover, trends toward a survival benefit with ZOL versus placebo were observed in patients with genitourinary cancers and were statistically significant in a retrospective analysis in the subset of patients with non-small cell lung cancer and high baseline NTX levels in the phase III trials. Previous exploratory analyses suggested that breast cancer patients with high baseline levels of NTX that normalize during therapy have improved survival versus patients with persistently elevated levels.

Changes in urinary NTX levels in patients with primary osteoporosis undergoing long-term bisphosphonate treatment

BackgroundBisphosphonates, antiresorptive drugs, are widely used to treat osteoporosis patients. However, recent reports indicated that several osteoporosis patients who underwent long-term bisphosphonate therapy subsequently developed severe suppression of bone turnover. We investigated whether urinary crosslinked N-telopeptide of type I collagen (NTX), a bone resorption marker, in osteoporosis patients was highly suppressed during long-term treatment with alendronate or risedronate. MethodsWe investigated 87 primary osteoporosis outpatients who were treated with alendronate or risedronate for more than 2 years. All patients were women, with an average age of 72.6 years. Altogether, 49 patients were treated with alendronate and 38 with risedronate, and the average administration period was 3.5 years. We defined high suppression as NTX being reduced <9.3 nmol bone collagen equivalent/ mmol•Cr and a 35% decrease from baseline. ResultsIn total, 11 of 87 patients (12.6%) had high NTX suppression based on the above criteria. The incidences of high suppression of NTX at 1,2,3,and 4 years after starting the treatment were 0%, 1.1%, 11.9%, and 4.7%, respectively. The average age, bone mineral density, and NTX values at baseline and the administration period were not associated with high suppression of NTX during alendronate or risedronate treatment. Regarding suppression of NTX during long-term treatment, there was no significant difference between alen-dronate and risedronate. ConclusionsThe results suggested that long-term treatment with bisphosphonates necessitates careful follow-up of the patients.

Survival benefits of zoledronic acid in patients with bone metastases from non-small cell lung cancer and high NTX levels: The role of BALP

19003 Background: In a clinical trial of zoledronic acid (ZOL) vs placebo in patients (pts) with bone metastases from solid tumors (not breast or prostate cancer; N = 773), ∼50% of pts had non-small cell lung cancer (NSCLC). Among all pts and NSCLC pts, ∼50% had high baseline levels of biochemical markers of bone resorption (N-telopeptide of type I collagen [NTX] ≥ 64 nmol/mmol creatinine) or formation (bone-specific alkaline phosphatase [BALP] ≥ 146 IU/L). Besides skeletal complication prevention, ZOL significantly prolonged survival in NSCLC pts with high baseline NTX, even after adjustment for other significant covariates (Hirsh V, et al. J Thorac Oncol. In press). However, the report did not include analyses by baseline BALP levels. Methods: Pts with NSCLC and bone marker data were included (n = 382), and analyses were performed by baseline NTX and BALP status. Kaplan-Meier survival estimates and Cox regression analyses of treatment by covariate interactions were performed. Results: In univariate analyses, variables associated with poorer survival were high pain score (P = .002), male sex (P = .020), low FACT-G score (P < .001), narcotic analgesics (P = .003), ECOG performance status > 1 (P < .001), high NTX (P = .003), high BALP (P = .020), creatinine ≥ 1.0 mg/dL (P = .032), and LDH ≥ 247 U/L (P = .005). In a multivariate model of treatment and baseline NTX and BALP, ZOL was associated with significantly increased survival vs placebo in the high-NTX subset (P = .02), but not in the high-BALP subset (P = .40). However, significant heterogeneity of benefits was detected between high- and low-BALP pts in the high-NTX subset (P = .04). Therefore, each group was assessed separately in Kaplan-Meier analyses. In the high-NTX subset, ZOL was associated with a 46% reduced risk of death in high-BALP pts (P = .006 vs placebo), but had no association with survival in low-BALP pts. ZOL was not significantly associated with survival in pts with low baseline NTX regardless of BALP status. Conclusions: Although prospective analyses are needed to elucidate the role of NTX and BALP, this analysis suggests that ZOL may prolong survival in a subset of NSCLC pts with advanced bone disease and high baseline levels of both markers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Oncology, GTx Inc., Merck, Novartis Oncology, Novartis Pharmaceuticals Inc. Novartis Oncology, Novartis Pharmaceuticals, Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. - Speakers Bureau

Meta-analysis of effects of zoledronic acid (ZOL) on survival in metastatic bone disease (MBD): Survival in patients with high bone turnover

20562 Background: ZOL is an integral component of therapy for patients (pts) with MBD to reduce the risk of skeletal-related events (SREs) and preserve physical function. Recent reports suggest that pts with high N-telopeptide of type I collagen (NTX) levels that normalize during therapy have improved survival compared with persistently high NTX (Lipton A, et al. Oncologist 2007, Cancer 2008). In this study we evaluate the outcomes of pts included in 3 placebo (PLA)-controlled trials of ZOL in solid tumors. Methods: Pts with MBD from solid tumors were included in randomized trials of ZOL (4 or 8/4 mg every 3–4 wk; n = 1071) vs PLA (n = 571) in addition to standard cancer therapies. Baseline NTX and bone-specific alkaline phosphatase (BALP) levels were available for 1345 pts (218 breast, 608 prostate, 519 other). Relative risks (RR) of death and associated 95% confidence intervals (CI) for ZOL vs PLA in the entire population (ITT), all pts with NTX and BALP data, and those ≥ and < the upper limits of normal (ULN) for NTX (64 nmol/mmol creatinine [Cr]) or BALP (146 IU/L) were assessed using a Cox regression model. Results: Survival was similar between treatment groups in the ITT population. However, although there was not statistically significant heterogeneity between the different bone marker groups, pts with NTX ≥ ULN who were treated with ZOL had significantly longer survival compared with PLA (Table 1). Further exploratory subset analyses revealed a 26.4% reduction in the risk of death for ZOL vs PLA among pts with especially high NTX levels (NTX > 100 nmol/mmol Cr [n = 498; RR = 0.736; 95% CI = 0.592, 0.916; P = .006]). Conclusions: The relationships between normalization of high baseline NTX at 3 mo and survival have been described previously. For the first time, this exploratory analysis investigates the effects of ZOL on survival in pts based on baseline bone turnover rates associated with MBD. Potential survival benefits are currently being investigated in multivariate models of the pooled dataset. Population ZOL, n PLA, n RR 95% CI P ITT 1071 571 0.939 0.828, 1.064 .323 Marker data 866 466 0.924 0.801, 1.067 .283 NTX < ULN 351 180 1.137 0.880, 1.469 .328 NTX ≥ ULN 518 286 0.828 0.696, 0.985 .034 BALP < ULN 304 162 1.039 0.795, 1.358 .781 BALP ≥ ULN 567 302 0.882 0.744, 1.046 .148 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. Novartis Pharmaceuticals Inc. - Speaker’s Bureau

Zoledronic Acid and Survival in Patients with Metastatic Bone Disease from Lung Cancer and Elevated Markers of Osteoclast Activity

Bone metastases from non-small cell lung cancer (NSCLC) are associated with skeletal-related events (SREs) and elevated levels of N-telopeptide of type I collagen (NTX) in some patients. Zoledronic acid (ZOL) reduces SRE risk and NTX levels. To assess effects of baseline variables, including NTX levels (normal = NTX < 64 nmol/mmol creatinine; high = NTX > or = 64 nmol/mmol creatinine), on treatment effects in NSCLC patients, a retrospective analysis was performed in NSCLC patients with bone metastases (N = 382) treated with ZOL or placebo every 3 weeks in a 21-month randomized clinical trial in patients with NSCLC or other solid tumors. Cox proportional hazards models assessed relative risks (RRs) of SREs, bone lesion progression, and death. Multivariate models analyzed covariate effects on survival. For both placebo- and ZOL-treated patients, high baseline NTX correlated with increased SRE risk (p = 0.068 and 0.012, respectively). Although high versus normal baseline NTX correlated with more than twofold increased risks of bone lesion progression and death in the placebo group (p = 0.039 and 0.001, respectively), correlations were weaker in the ZOL group (RR = 1.38; p = 0.0186 and RR = 1.27; p = 0.142, respectively), suggesting an interaction effect of ZOL and baseline NTX. Among patients with high baseline NTX, ZOL significantly reduced the RR of death by 35% versus placebo (p = 0.024). Per multivariate analysis, ZOL treatment (p = 0.005), higher lymphocyte count (p = 0.011), performance status 0 to 1 (p = 0.012), and absence of narcotic use (p = 0.016) correlated with improved survival. This retrospective analysis revealed statistically significant correlations between ZOL and increased survival versus placebo in NSCLC patients and high baseline NTX levels.

OC10. Prognosis and skeletal disease course in patients with bone metastases from breast cancer (BC) and normal baseline levels of N-telopeptide of type I collagen (NTX)

Background: High baseline NTX has been correlated with high risks of skeletal-related events (SREs) and death in BC patients with bone metastases. However, disease course has not been well characterized in BC patients with bone metastases but normal baseline NTX.

Predictors for Skeletal-Related Events in Patients with Advanced Multiple Myeloma.

Most patients with advanced multiple myeloma (MM) develop bone lesions during their disease course. Myeloma bone disease can result in potentially debilitating and life threatening skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, the need for palliative radiotherapy (RT) or surgery to bone, and hypercalcemia of malignancy. Bone-targeted therapies that prevent or delay SRE onset may maintain quality of life (QOL) and functional independence in patients with advanced MM. Yet, the risk factors for SREs in this patient population are not fully understood. Exploratory analyses were conducted to identify potential SRE risk factors in patients with bone lesions from MM who received either zoledronic acid or pamidronate every 3 to 4 weeks for up to 24 months in a large, randomized trial. Patients with complete baseline demographics, disease characteristics, and markers of bone metabolism information available were included (n=282). Dichotomous variables included sex, race (white/other), narcotic analgesics (yes/no), Eastern Cooperative Oncology Group performance status (active/impaired), prior SRE (yes/no), and values with a defined upper limit of normal (creatinine, lymphocyte %, hemoglobin, serum glutamic oxaloacetic transaminase, albumin, lactate dehydrogenase [LDH], and calcium). Continuous variables included age, weight, cancer duration, Functional Assessment of Cancer Therapy-General score, Brief Pain Inventory (BPI) score, and bone markers (eg, urinary N-telopeptide of type I collagen [NTX], deoxypyridinoline [DPD]). Paraprotein type was also included. Univariate and multivariate analyses to determine relative risks (RR) for reduced time to first SRE associated with baseline variables using Cox regression models were developed, and those that were not significant at the 5% level were removed by backward elimination to generate a reduced model. In the reduced multivariate model, lower weight (RR=0.94 per 5-kg increase; P=.021), higher BPI scores (RR=1.16 per 1-unit increase; P < .001), race other than white (RR=0.60; P=.028), need for narcotic analgesics (RR=1.61; P=.017), and high levels of NTX (RR=1.68 per 100-nmol/mmol creatinine increase; P=.005) significantly correlated with reduced time to first SRE. Pathologic fracture and RT to bone were the most common SREs; in multivariate models, lower weight and higher BPI scores were associated with increased RRs of both fractures and RT to bone. Race and DPD levels were also significant covariates for fractures, whereas high levels of LDH correlated significantly with need for RT. Because bone resorption marker levels were significant covariates, the correlation between baseline NTX and time to first SRE was assessed. High baseline NTX (≥ 50 nmol/mmol creatinine) was associated with increased risk of shorter time to first SRE: by a significant 67% in the zoledronic acid group (n=210; P=.015) and by a 57% trend in the pamidronate group (n=108; P=.114). Taken together, lower weight and pain parameters (eg, BPI or narcotic analgesics) correlated consistently with skeletal morbidity risks in patients with advanced MM. Treatments that facilitate the restoration of bone homeostasis, as evidenced by bone marker normalization, may reduce the risk of SREs, thus maintaining QOL in this patient population.

Serum crosslinked N‐terminal telopeptide of type 1 collagen for evaluation of bone loss in hemodialysis patients using dual‐energy x‐ray absorptiometry

AbstractBACKGROUNDUseful markers of bone resorption are needed for hemodialysis (HD) patients with renal osteodystrophy. The present study investigated the use of a new immunoassay for the crosslinked N‐terminal telopeptide of type 1 collagen to assess bone loss in HD patients.METHODSForty‐seven male and 19 female patients were enrolled in this study. Their mean age was 64 years, and the mean duration they had been receiving HD was 110 months at the time of investigation. Their mean body mass index (BMI) was 21 kg/m2. Serum levels of N‐terminal telopeptide of type 1 collagen (NTx) and of total calcium (Ca), phosphorus (P), alkaline phosphatase (Alp), and intact parathyroid hormone (PTH) were measured. Bone mineral density (BMD) of the distal one‐third of the radius was examined by dual‐energy x‐ray absorptiometry.RESULTSSerum levels of NTx, Ca, P, Alp, and intact PTH were 68.9 nmol BCE/L, 4.5 mEq/L, 6.3 mg/dL, 248 IU/L, and 241 pg/mL, respectively. BMD was positively correlated with BMI (r = 0.24, p &lt; .05) and negatively correlated with NTx (r = −0.27, p &lt; .05) and duration of HD (r = −0.24, p &lt; .05).CONCLUSIONSSerum NTx could be a useful marker of bone resorption in patients with renal osteodystrophy. If high serum NTx is found, then treatment for prevention of bone loss should be considered.

Effect of risedronate on high-dose corticosteroid-induced bone loss in patients with glomerular disease

Corticosteroids are often used for the treatment of glomerular diseases. We examined whether bisphosphonate or vitamin D3 has beneficial effects on bone mineral density (BMD) in patients with glomerular diseases being treated with high-dose corticosteroids, including pulse therapy. Thirty-eight patients (19 men and 19 women, aged 42 +/- 16 years) were randomized into three groups: bisphosphonate alone (risedronate 2.5 mg/day, group R, n = 12), vitamin D3 alone (alfacalcidol 0.5 mug/day, group A, n = 15) and the combination of both agents (group R+A, n = 11). BMD at the lumbar spine was measured before and 12 months after treatment. The biochemical parameters of bone metabolism were assessed before and 3, 6 and 12 months after treatment. In group R+A, BMD was significantly increased (+2.0%), whereas BMD was significantly decreased in group A (-5.6%). The BMD in group R did not show a significant change. In patients treated with steroid-pulse, BMD was decreased in groups R and A. In group R+A, BMD was significantly increased (+2.1%). Serum osteocalcin and alkaline phosphatase levels, markers of bone formation, were significantly decreased in all groups. Urinary crosslinked N-telopeptide of type I collagen (NTx) levels, a marker of bone resorption, were decreased in groups R and R+A. In patients with decreased BMD, the urinary NTx levels at baseline were significantly higher than the patients with increased BMD. Bisphosphonate might be beneficial for the prevention of steroid-induced bone loss in patients with glomerular diseases compared with vitamin D3. The combined therapy may be more effective, especially in patients treated with high-dose corticosteroids, including pulse therapy. A high urinary NTx level before receiving corticosteroids might be a predictive marker of the loss of BMD.

Effects of zoledronic acid on survival in patients with lung cancer and high baseline N-telopeptide (NTX) levels: Stratified by baseline bone alkaline phosphatase (BALP)

7228 Background: Recently, it was shown that patients (pts) with bone metastases from lung cancer who had high NTX or BALP levels on study had a higher risk for skeletal-related events (SREs) and death compared with pts with low NTX or BALP. Zoledronic acid has been shown to prevent SREs; however, it is unknown whether there is a secondary survival benefit in this pt population. To assess the potential effect of zoledronic acid on survival in pts with bone metastases from lung cancer and high baseline NTX, we conducted a retrospective analysis of pts in a large, randomized, controlled trial. Methods: Patients with lung cancer and bone metastases were randomized to receive either 4 mg zoledronic acid or placebo for a total of 21 months. Survival data were evaluated in pts who had a high baseline NTX level (≥ 64 nmol/mmol) and baseline BALP level (retrospectively stratified by baseline BALP level according to these criteria: normal BALP &lt; 146 U/L and high BALP ≥ 146 U/L). The relative risk (RR) of death was calculated for each pt group and for pts with high NTX levels overall compared with placebo. Results: The pts with high NTX levels (n = 144; men, 65% women, 35%) had a median age of 64 years. Among these pts, the RR of death was significantly reduced by 35% in pts who received zoledronic acid compared with placebo (RR = 0.650; P = .0244). The RR of death on study for pts who had both high baseline NTX and BALP levels (n = 97) was also significantly reduced by 46% in pts who received zoledronic acid compared with placebo (RR = 0.537; P = .0059). Among pts who had high baseline NTX and normal BALP levels (n = 47), the RR of death was similar between treatment groups (RR = 1.012; P = .9736). Conclusions: High levels of bone resorption may correlate with an increased risk of SREs and death. Zoledronic acid reduces bone turnover and the risk of SREs and may delay the progression of bone lesions. This retrospective analysis suggests that treatment with zoledronic acid may improve survival compared with placebo in pts with lung cancer who have high levels of bone metabolism, warranting further study in either other database analyses or prospective trials. [Table: see text]