Onset Of Skeletal-related Events Research Articles

Prospective analysis of the association between skeletal‑related events and quality of life in patients with advanced lung cancer (CSP‑HOR13)

A prospective study has previously reported on the incidence of bone metastasis (BM) and skeletal-related events (SREs) in patients with advanced lung cancer. The aim of the present study was to prospectively investigate how the quality of life (QOL) of patients with advanced lung cancer was affected by SREs. Patients with stage IIIB or IV non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) at any stage were followed up every four weeks to determine if they had developed SREs. QOL questionnaires were conducted at enrollment, at 3- and 12-months later and at 1 month after the onset of SREs, using QOL scores including the EuroQOL-5 Dimension (EQ-5D), Functional Assessment of Cancer Therapy-General (FACT-G) and activities of daily living (ADL) scores obtained by the Barthel Index. A total of 274 patients were enrolled in the study. At enrollment the EQ-5D and Barthel Index scores were lower in patients with SREs compared with patients without SREs. A chronological analysis revealed no statistically significant changes in either QOL or ADL in any of the patients. For 14 patients in whom QOL data was collected following the onset of SREs, the evaluation undertaken on the four subscales of the FACT-G revealed a significant decline in emotional functioning following the onset of SREs.

Epidermal growth factor receptor is associated with the onset of skeletal related events in non-small cell lung cancer.

BackgroundBone metastasis and skeletal related events (SREs) are common in non-small cell lung cancer (NSCLC). Patients with mutant epidermal growth factor receptor (EGFR) could benefit from tyrosine kinase inhibitors (TKIs). However, it is unclear whether SRE is influenced by EGFR status. We aimed to evaluate the correlation of EGFR status and TKIs with the incidence of SREs.MethodsWe conducted a retrospective study of stage IV NSCLC patients with bone metastasis. Incidence rate of SREs was collected and was compared using chi-square test. Logistic-regression analysis was used to identify the risk factors predicting the incidence of SREs.Results410 eligible patients were enrolled in the study. 49.0% were detected with EGFR mutation. 49.8% of patients received EGFR-TKIs therapy prior to the onset of SREs. 42.7% experienced at least one SRE. Patients who were treated with TKIs held lower incidence of SREs than patients who were not treated with TKIs (23.5% vs 61.7%, p<0.001). Multivariate analysis showed that poor performance status (OR 5.550, 95%CI 2.290-13.450; p<0.001) and mutant EGFR (OR 3.050, 95%CI 1.608-5.787, p=0.001) were independent risk factors predicting the onset of SREs, while the usage of TKIs (OR 0.102, 95%CI 0.054-0.193, p<0.001) was a protective factor of SREs in NSCLC patients with bone metastasis.ConclusionsThis study indicates that the incidence of SREs is common in both patients with and without EGFR mutation. Poor performance ability and mutant EGFR imply higher risks of SREs, while the usage of TKIs may be a protective factor of SREs.

P1.06-025 Analysis of Risk Factors for Development of Skeletal-Related Events in Women with Bone Metastases from NSCLC and Breast Cancer

Bone metastases (BM) are common (up to 50% of cases) in patients with advanced non-small cell lung cancer (NSCLC) and other malignancies, including prostate cancer and breast cancer (BC). In patients with BMs, the onset of skeletal-related events (SREs), such as pathological fracture, malignant hypercalcemia, or spinal cord compression requiring surgery or radiation therapy, seriously affects the quality of life of patients and overall survival. The purpose of this study was to analyze the risk factors (RFs) for development of SREs in women with advanced NSCLC and BC, with the aim of highlighting the differences (if any) between the two groups of patients. The medical records of 16 women with BMs from NSCLC (Group A) and 15 women with BMs from luminal-type BC (Group B) were reviewed. The following RFs have been considered: age >65 years, ECOG performance status (PS) <2, the presence of extra-skeletal metastases (ESM) or hypercalcemia (>2.65 mmol/L), and number of BMs >1. Odds ratio (OR) estimates and the relative 95% confidence interval (CI) were calculated. A p-value level <0.05 was considered statistically significant. During follow-up, 5 (33.3%) Group A and 111 (68.7%) Group B patients developed SREs (OR=4.40, p=0.04), respectively. The results are reported in the Table. No significant difference (p=NS) was found between groups in relation to ECOG-PS, ESM or hypercalcemia, and number of BMs. Only the age >65 years (OR=0.22, p=0.04) represented a weak significant risk factor.Tabled 1ParameterNSCLCBCOR95% CIp-valueNo. of patients1516---Skeletal-related events33.3%68.7%4.400.97-19.850.04Age >65 years73.3%37.5%0.220.05-1.010.04ECOG-Performance status >240.0%18.8%0.340.07-1.760.25Extra-skeletal metastases26.7%43.7%2.140.47-9.700.32Malignant hypercalcemia26.7%12.5%0.390.06-2.550.39Multiple bone metastases53.5%37.5%0.520.12-2.200.38 Open table in a new tab Women with BMs from NSCLC has a reduced risk for development of SREs compared to those with BC, but elderly (>65 years) patients require a closer surveillance, and a precocious bisphosphonate treatment could be suggested.

Cost-effectiveness Analysis of Denosumab in the Prevention of Skeletal-related Events in Patients with Prostate Cancer in Kazakhstan.

IntroductionBone mass loss (BML) is one of the adverse effects of oncological chemotherapy, especially in cases of hormonal types of cancer, such as a prostate cancer (PC). BML is strongly associated with skeletal-related events (SREs), therefore decreasing the quality of patient’s life. Denosumab shows an advantage over zoledronic acid (ZA) in delaying the first onset of SREs and subsequent SREs in adults with PC in several phase III clinical trials. Since generic ZA recently became available, the purpose of the present study was to assess the cost-effectiveness of denosumab vs. brand or generic ZA in the prevention of SREs in Kazakhstani patients with PC.MethodsA Markov model was constructed in Tree-Age Pro 2013 software program with 4-week model cycles to analyze the cost-effectiveness of the treatments from the perspective of Ministry of Health (MoH) over a 10-year PC cohort. Direct costs (in Kazakhstani monetary units “tenge” in 2014) included costs of drug, SRE (pathologic fracture, surgery to bone, radiation to bone, spinal cord compression), and adverse events treatment. All costs were discounted for 3% per year. Effectiveness was appraised based on the number of SREs. Health states were defined according to SRE occurrence, SRE history, and death. The model assumed that a maximum of 1 SRE could occur in each cycle. Transition probabilities were derived from the relevant phase III trials. Results were present in the incremental total cost per SRE avoided. One-way sensitivity analyses were performed to examine the robustness of the model.ResultsOver the 10-year period, denosumab incurred 103,091 tenge higher costs than brand ZA, 677,133 tenge higher costs than generic ZA, and 0.58 fewer SREs per patient with PC. The estimated incremental total direct costs per SRE avoided with the use of denosumab were 177,743 tenge (instead of brand ZA) and 1,167,470 tenge (instead of generic ZA). Results were robust to one-way sensitivity analyses.ConclusionsWith the assumption that brand and generic ZAs are equally effective in the prevention of SREs in PC patients, denosumab seems to be a cost-effective alternative for brand ZA (insignificant difference in costs – less than 5%) and a costly alternative for generic ZA from the perspective of MoH of Kazakhstan.

Targeted treatments of bone metastases in patients with lung cancer.

Until now ~30–40% of patients with advanced lung cancer develop bone metastases, but as the newer therapies are extending survival, the chance of developing bone metastases increases. Bone metastases cause skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia, which can have debilitating consequences affecting patients’ health-related quality of life (HR-QOL) and performance status (PS). Poor PS then prevents the patients to receive further lines of treatments, which are available today. SREs are associated with increased economic costs. In one clinical trial, the median time to first SRE was only 5 months. Early detection of bone metastases can prevent SREs and avoid inappropriate implementation of major surgery or chemoradiation therapy. With the new generation bisphosphonate zoledronic acid (ZA) or denosumab (anti-RANKL activity), one can reduce the number of patients who experience SREs, decrease the annual incidence of SREs and delay the median time to first SRE. These agents are effective even after the onset of SREs. They are well tolerated, with manageable side effects. The biochemical markers of bone metabolism especially N-telopeptide of type I collagen and bone specific alkaline phosphatase (BALP) can be both prognostic and predictive markers for the patients with bone metastases from non-small cell lung cancer (NSCLC). Anticancer activity of ZA and denosumab further supports their use as soon as bone metastases are diagnosed in patients with NSCLC. Further trials will inform us about the efficacy of these agents for prevention of bone metastases and even about possible effects on visceral metastases.

Comparison of the anti-tumor effects of denosumab and zoledronic acid on the neoplastic stromal cells of giant cell tumor of bone

Denosumab and Zoledronic acid (ZOL) are two antiresorptive drugs currently in use for treating osteoporosis. They have different mechanisms of action but both have been shown to delay the onset of skeletal-related events in patients with giant cell tumor of bone (GCT). However, the anti-tumor mechanisms of denosumab on the neoplastic GCT stromal cells remain unknown. In this study, we focused on the direct effects of denosumab on the neoplastic GCT stromal cells and compared with ZOL. The microscopic view demonstrated a reduced cell growth in ZOL-treated but not in denosumab-treated GCT stromal cells. ZOL was found to exhibit a dose-dependent inhibition in cell growth in all GCT stromal cell lines tested and cause apoptosis in two out of three cell lines. In contrast, denosumab only exerted a minimal inhibitory effect in one cell line and did not induce any apoptosis. ZOL significantly inhibited the mRNA expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in two GCT stromal cell lines whereas their protein levels remained unchanged. On the contrary, denosumab did not regulate RANKL and OPG expression at both mRNA and protein levels. Moreover, the protein expression of Macrophage Colony-Stimulating Factor (M-CSF), Alkaline Phosphatase (ALP), and Collagen α1 Type I were not regulated by denosumab and ZOL either. Our findings provide new insights in the anti-tumor effect of denosumab on GCT stromal cells and raise a concern that tumor recurrence may occur after the withdrawal of the drug.

Natural history of malignant bone disease in gastric cancer: Final results of a multicenter bone metastasis survey.

4091 Background: Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature few data on the natural history of bone disease in this malignancy are available. Methods: A retrospective, observational multicenter study aimed to define the natural history of GC patients with bone metastasis was conducted in 22 Italian hospital centres in which these patients received diagnosis and treatment of disease from 1998 to 2011. Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. Results: Median time to bone metastasis was 8 months (CI 95%, 6.125–9.875 months) considering all included patients. Median number of SREs/patient was one; less than half of the patients (31%) experienced at least one event and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid (ZOL) before the first SRE, median time to its appearance was significantly prolonged compared to control (7 months vs 4 months for control; P:0.0005). Conclusions: To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Furthermore, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis.

Zoledronic acid in lung cancer with bone metastases: a review

Lung cancer remains the leading cause of cancer mortality worldwide and bone metastases develop in approximately 30–40% of cases. Bisphosphonates are a key therapy for bone metastases; zoledronic acid is the only bisphosphonate with efficacy in preventing, reducing the incidence and delaying the onset of skeletal-related events controlling bone pain. Several bone metabolism markers indicate bone resorption activity, linking with prognosis and efficacy of zoledronic acid. Zoledronic acid has a well-established tolerability profile and can be administered safely as long-term therapy, although preventive measures are needed to avoid some severe side effects (nephrotoxicity and osteonecrosis of the jaw) found in a small number of patients receiving long-term therapy. Currently, lung cancer patients with bone metastases are candidates to receive zoledronic acid in clinical practice with demonstrated benefits and safety preserving quality of life. Additional roles in anticancer activity deserve attention and are under investigation.

Castrate-resistant Prostate Cancer—Recent Advances in Therapy and Future Perspectives

For many years, few therapeutic options were available for the treatment of advanced prostate cancer. Recent advances in our understanding of the molecular biology of prostate cancer, particularly in the transition to castrate resistant disease, have led to the development of more potent and selective endocrine therapies. In addition, elucidation of the many factors in the bone microenvironment that promote the development and subsequent progression of skeletal metastases has led to the discovery of new bone-targeting agents that can delay the onset of skeletal related events and improve quality of life and survival. This review will highlight recently approved novel agents as well as others currently under investigation for the treatment of castrate-resistant prostate cancer (CRPC).

Abstract PD07-09: Zoledronate versus ibandronate comparative evaluation (ZICE) trial - first results of a UK NCRI 1,405 patient phase III trial comparing oral ibandronate versus intravenous zoledronate in the treatment of breast cancer patients with bone metastases.

Abstract Introduction Bone metastases in patients with breast cancer have serious effects on health including pain, poor mobility, skeletal fractures, spinal cord compression and the need for radiotherapy/surgery. The introduction of intravenous (IV) bisphosphonates, such as zoledronic acid (Z) has significantly delayed the onset of skeletal-related events (SRE). However, prolonged IV bisphosphonates place burdens upon patient and hospital, and can also cause renal and acute phase toxicities. Ibandronic acid (I), a third generation amino-bisphosphonate in its oral form has previously been compared with placebo and was shown to be well tolerated and effective. Indirect comparisons with IV Z indicated similar efficacy in reducing bone events, but adverse events were overall comparable with placebo. One might therefore assume that oral ibandronate would be more acceptable to patients, and the ZICE Trial is the only large scale direct randomised comparison between IV Z and oral I to report. Methods Between January 2006 and October 2010, 1405 newly diagnosed metastatic breast cancer patients with proven bone metastases were randomised 1:1 to IV Z (4mg 15 min infusion every 3–4 weeks) or oral I (50mg per day) for up to 96 weeks. All patients were prescribed daily calcium &amp; vitamin D supplementation, and patients with current active dental problems including infection were excluded. Patients also received chemotherapy, and or endocrine therapy as determined by their physician. The primary objective was to demonstrate non-inferiority of oral I in comparison with IV Z in terms of the SRE rate, defined as the number of SREs reported per year (using multiple event analysis). Secondary endpoints included time to 1st SRE, proportion of patients with SRE, Pain Scores, side effect profiles including ONJ and renal toxicities, quality of life and Health resources and overall survival. The trial was run under the auspices of the NCRI, sponsored by Velindre NHS Trust, coordinated by the Wales Cancer Trials Unit, funded by an educational grant from Roche and peer reviewed/endorsed by Cancer Research UK (CRUKE/04/022). Results At the time of this analysis the last randomised patient had completed 96 weeks of therapy, median follow up was 18.4 months and total number of SREs was 865 (468 in I and 397 in Z). For the primary objective, the SRE rate was 0.543 and 0.444 in I and Z groups respectively (Hazard ratio, 1.22; 95% CI, 1.04 to 1.45; P = .017). Ibandronate failed to meet the criteria for non-inferiority to Zoledronate, but was similar in delaying time to first SRE (hazard ratio, 1.11; 95% CI, 0.94 to 1.31; P = .233). Overall survival (disease progression), was very similar between groups but renal AEs occurred more frequently with Z than I; Compliance with oral therapy was 82%. ONJ rate was very low in both arms (0.71%, I; 1.29%, Z; P = 0.28). Conclusion Oral I is inferior to Z in terms of the SRE rate in metastatic breast cancer patients with bone metastases, but is similar to Z in delaying time to first SRE. Both drugs had acceptable safety profiles, with adverse events consistent with those reported previously. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-09.

Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid

Denosumab (Dmab) and zoledronic acid (ZOL) are antiresorptive agents, with different mechanisms of action, that are indicated for delaying the onset of skeletal-related events in patients with bone metastases from solid tumors. Clinical and preclinical data suggest that ZOL may have also anti-angiogenic activity; however, the effects of Dmab (a fully humanized antibody against the receptor activator of nuclear factor kappa B ligand) on angiogenesis are largely unknown. The objective of this study was to compare the potential anti-angiogenic activity of Dmab with that of ZOL in preclinical models. Dmab (0.31 to 160 μM) had no effect on the viability of human MDA-MB-436 and CG5 breast cancer cells or human umbilical vein endothelial cells (HUVECs) and no effect on tubule formation or invasion of HUVECs. In contrast, ZOL (0.31 to 160 μM) decreased the viability of breast cancer and HUVECs in a time- and concentration-dependent manner and also inhibited HUVEC tubule formation and invasion. In vivo, ZOL (20 μg/mouse for three times a week for three consecutive weeks) inhibited angiogenesis in Matrigel plugs and inhibited the growth and neo-angiogenesis of CG5 xenografts in athymic nude mice. In contrast, Dmab (10 mg/Kg twice a week for 4 consecutive weeks) had no effect on Matrigel vascularization or xenograft growth in this model. These findings support the potential antiangiogenic and anticancer activity of ZOL in vitro and in vivo and further suggest that Dmab does not have antiangiogenic activity. Additional studies are needed to elucidate the potential anticancer activity of Dmab.

Chairperson's introduction

Prostate cancer (PCa) is the most frequently detected cancer in the European Union in men above 50 years of age. The updated results of the GLOBOCAN project report for Europe a 2008 incidence of 323,790 cases and 71,027 deaths [1]. Despite increased awareness of PSA screening and early detection, 30% of the patients will be diagnosed with or progressing to a stage requiring systemic therapy. Since the seminal works of Huggins & Hodge in 1941, androgen deprivation (ADT) by means of surgical castration, LHRH agonist or antagonist, or oestrogens has been the unchallenged upfront treatment of advanced PCa [2]. Initially indicated for symptomatic patients, it is now widely prescribed in men with asymptomatic locally advanced disease or adjuvant to external beam radiation therapy and radical prostatectomy. Except for the adjuvant setting, ADT is considered a palliative therapy. Indeed, despite tumour response of great magnitude, most PCa will adapt to the low testosterone environment and further growth will occur. This phase of adaptation has been called over the years androgen independence, hormone resistance, or, more recently, castration resistance. Until 2004, the development of castration-resistant PCa (CRPC) was a uniformly lethal event, mainly characterised by the development of bone metastases and their complications, skeletal-related events (SREs). In 2004, two drugs had a profound impact on the treatment of this disease: docetaxel, a taxane chemotherapy, which prolonged survival by about three months, and zoledronic acid, a bone-protecting bisphosphonate, which delays the onset of SREs [3]. This was the beginning of a new era for the treatment of CRPC. The work initiated by many scientists around the world to better understand the pathophysiology of CRPC was starting to pay off. One of the main observations was that, although the tumour develops in a low-testosterone environment, the androgen receptor remains the driving force of the cancer growth. Physicians who commonly prescribed several lines of hormonal agents in these patients had already intuitively perceived this. In addition, several critical pathways involved in CRPC have been characterised and, more importantly, have been used to develop novel therapies [3]. Two successful examples of such bench to bedside strategies are the recently approved denosumab, which targets the Rank/RankL/ OPG pathway, and abiraterone, a potent inhibitor of intratumoral steroidogenesis. As a consequence, the field of CRPC has become a very complex area. This education programme will provide recent insights helping the clinician to apprehend that complexity and understand its challenges. First, we will review the current knowledge on the physiopathology underlying the conversion from a hormone-naive to a castration-resistant PCA. Then, Drs De Bono and Sternberg will illustrate how that new knowledge has led to the development of new hormonal and non-hormonal agents. Finally, Dr Chauchereau will illustrate how animal engineering has built on that knowledge to provide better tools for researchers.

Bone Metastases From Advanced Cancers

Bone metastases are associated with considerable morbidity and can result in skeletal-related events (SREs), including pathologic fractures, the need for palliative radiotherapy, spinal cord compression, the need for surgery to bone to prevent or treat a pathologic fracture or spinal cord compression, and hypercalcemia of malignancy. Such SREs have been associated with decreases in survival and increases in healthcare costs. Skeletal morbidity and bone pain from metastases can also reduce patients' functional capacity and undermine their quality of life. Patients who develop bone metastases from advanced cancers commonly receive bisphosphonates to not only delay the onset of SREs and reduce their frequency but also provide clinically meaningful palliative effects for bone pain. Ongoing research may lead to improvements in skeletal health monitoring and management for patients with malignant bone disease.

Biochemical indices of bone turnover in stroke patients is comparable to that of hip fracture patients

Metastatic bone disease in patients with advanced cancer is frequently associated with skeletal complications. These can be debilitating, causing pain, impaired functioning and decreased quality of life, as well as reduced survival. This review considers how the management of metastatic bone pain might be optimised, to limit the considerable burden it can impose on affected patients. Cancer-related pain is notoriously under-reported and under-treated, despite the availability of many therapeutic options. Non-opioid and opioid analgesics can be used; the latter are typically administered with radiotherapy, which forms the current standard of care for patients with metastatic bone pain. Surgery is appropriate for certain complicated cases of metastatic bone disease, and other options such as radiopharmaceuticals may provide additional relief. Treatments collectively referred to as bone-targeted agents (BTAs; bisphosphonates and denosumab) can offer further pain reduction. Initiation of therapy with BTAs is recommended for all patients with metastatic bone disease because these agents delay not only the onset of skeletal-related events but also the onset of bone pain. With evidence also emerging for pain control properties of new anticancer agents, the potential to individualise care for these patients is increased further. Optimisation of care depends on physicians' thorough appreciation of the complementary benefits that might be achieved with the various agents, as well as their limitations. Appropriate anti-tumour treatment combined with early initiation of BTAs and adequate analgesia plays a key role in the holistic approach to cancer pain management and may minimise the debilitating effects of metastatic bone pain.

MP-08.23: Zoledronic acid produces benefits in patients with early malignant bone disease from hormone-refractory prostate cancer

The majority of patients with advanced prostate cancer (PC) develop bone metastases that can result in skeletal-related events (SREs) including pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and radiotherapy or surgery to bone. Zoledronic acid has demonstrated efficacy in reducing and delaying SREs in patients with hormone-refractory prostate cancer (HRPC). Bone metastases in patients with recurrent PC are now often diagnosed earlier in the course of disease progression, often before the onset of SREs or bone pain.

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.