Urinary NTX Levels Research Articles

Strontium-89 plus zoledronic acid versus zoledronic acid for patients with painful bone metastatic breast cancer

β-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases. A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates. Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89. This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated.

Retraction Note: Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteoporosis.

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis.

Retraction Note to: Effect of alendronate on bone mineral density and bone turnovermarkers in post-gastrectomy osteoporotic patients.

Alendronate decreases the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX; about 45% at 3 months) and serum levels of alkaline phosphatase (ALP; about 27% at 24 months), leading to an increase in lumbar spine bone mineral density (BMD; about 9% at 24 months) in postmenopausal Japanese women with osteoporosis. However, the effectiveness of oral bisphosphonates on osteoporosis remains to be established in patients who have undergone a gastrectomy. The objective of the present case series study was to examine the effect of alendronate on BMD and bone turnover markers in post-gastrectomy osteoporotic patients. Sixteen patients (3 men and 13 postmenopausal women) with osteoporosis, who had undergone a gastrectomy (mean age: 69.1 years), were recruited in our outpatient clinic. All the patients were treated with alendronate (5 mg daily or 35 mg weekly) for 24 months. The effects of alendronate on lumbar spine (women) or total hip (men) BMD and urinary NTX and serum ALP levels were examined. A total or partial gastrectomy had been performed for eight patients each. The mean duration after surgery was 16.0 years. With alendronate therapy, urinary NTX levels significantly decreased at 3 months (−27.0%). Serum ALP levels decreased (−12.1%) and lumbar spine BMD increased (+5.2%), but total hip BMD did not significantly change (+0.6%) at 24 months. No severe adverse events were observed, and alendronate therapy was well tolerated. These results suggest that alendronate mildly increases lumbar spine BMD by mildly reducing bone turnover in osteoporotic patients after a gastrectomy.

SUN-412 Graves’ Disease Displayed as a Risk Factor of Vertebral Fracture Even in Premenopausal Women

BackgroundHyperthyroidism is a known risk factor for osteoporosis and fractures especially in older men and postmenopausal women. However, it remains unclear whether younger patients with Graves’ diseases are at a higher risk of fracture compared to healthy individuals.ObjectiveThis study aimed to clarify whether premenopausal women with Graves’ disease represents a risk factor for vertebral fracture (VF).Patients and MethodsWe enrolled 30 premenopausal women (mean age, 32 ± 10 years) who were diagnosed with Graves’ disease at our institution between April 2007 and December 2017. We also enrolled 40 healthy control women who visited our hospital. The control subjects were confirmed to have no endocrine disease or any condition that might affect bone metabolism. None of the study subjects had taken drugs known to influence bone and calcium metabolism such as vitamin D, bisphosphonates, or glucocorticoids. Also, none has taken an oral contraceptive. Serum and urinary biological parameters, alkaline phosphatase (ALP), glycosylated hemoglobin (HbA1c), creatinine, serum calcium, total cholesterol, intact parathyroid hormone, free triiodothyronine (Free T3), free thyroxin (Free T4), thyroid-stimulating hormone (TSH) and urinary type I collagen cross-linked N-telopeptides (NTX; a bone resorption marker) were compared between the groups. Bone mineral density (BMD) of the lumbar spine and femoral neck was determined using dual-energy X-ray absorptiometry and vertebral fractures were diagnosed from lateral X-rays of the thoracic and lumbar spine. The chi-square and unpaired t-tests for two groups comparison were utilized to determine the statistical significance (P < 0.05). Multiple logistic regression analyses were proceeded after adjustments for variables.ResultsPatients with Graves’ disease displayed the higher ALP, eGFR, Ca, free T3, free T4 and urinary NTX levels, and lower body mass index (BMI), Alb, total cholesterol and intact PTH compared to controls.The prevalence of VFs was significantly higher in patients with Graves’ disease (20.0%) than in controls (2.5%, <0.05). Such association remained significant even after adjustment for age, BMI, ALP, eGFR and free T3, but except for BMD. Among premenopausal patients with Graves’ disease, the values of several parameters, such as BMI, ALP, HbA1c, serum Ca, intact PTH and BMD and the prevalence of thyroid related antibodies did not differ significantly between those with and without VF; subjects with VF were older and exhibited lower free T3, free T4 and urinary NTX levels compared to subjects without VF. The mean value of lumbar BMD T score in subjects with VF among premenopausal patients with graves’ disease was -1.0, indicating osteopenia.ConclusionsVF risk could be elevated even in the premenopausal women with Graves’ disease, although the BMD risk levels is not equivalent to that of osteoporosis.

Zoledronik asit osteoporozlu β-talasemi hastalarında kemik mineral yoğunluğunu arttırır: Bir vaka kontrol çalışması

Purpose: This study addresses the efficacy of zoledronic acid treatment in osteoporotic patients with β-thalassemia.Materials and Methods: Thirty-nine thalassemic patients were enrolled in this study. Bone mineral density was measured using Dual energy x-ray absorbtiometry (DEXA), and biochemical markers of osteoporosis in serum and urine were measured at 0, 6, and 12 months of treatment. Patients with thalassemia were randomly received either zoledronic acid 4 mg IV once every six months or calcitriol 0.25 mcg / day for 12 months. A subgroup analysis was also performed according to gonadal status. Results: There were 21 males and 18 females, mean age of 23.1 ± 1.3 and bone age of 16.3±0.35 years. At the end of 12 months, bone mineral densities of the lumbar vertebra and femoral neck significantly increased in the zoledronic acid group. In patients with hypogonadism who received hormone replacement therapy, t-scores significantly increased. Serum NTX levels indicated significant increase in both treatment groups compared with the control group at the end of the treatment. A significant increase was obtained in urinary NTX level in hypogonadal patients who received zoledronic acid, and in serum NTX and IGF-1 levels in normogonadal patients who received calcitriol. Conclusion: In our study, zoledronic acid resulted in significant improvement in bone mineral density and t-scores. This improvement was in correlation with IGF-1 levels.

Maternal type 1collagen N-terminal telopeptide levels in severe hyperemesis gravidarum

BackgroundNausea and vomiting occur 50–90% during the first trimester of pregnancy. However, patients with hyperemesis gravidarum (HG) may be hospitalized at an incidence rate of 0.8–2% before the 20th week of gestational age. The symptoms generally start during the 5–6th gestational weeks, reaching the highest degree during the 9th week, and decline after the 16–20th weeks of gestation. Clinical findings are proportional to the severity of the disease and severe HG is characterized with dehydration, electrolyte imbalance, and nutritional deficiency as a result of vomiting.MethodsThe study population consisted of two groups of pregnant volunteers at 5–12 weeks of gestation: a severe HG group and a control group. The HG severity was scored using the Pregnancy-Unique Quantification of Emesis (and nausea) (PUQE).The serum levels of the maternal Ca, parathyroid hormone (PTH), Na, K, blood urea nitrogen(BUN), creatinine, vitamin D(25OHD3), and the maternal urine NTx levels were compared between the groups.ResultsIn total, 40 volunteers were enrolled in this study: 20 healthy pregnant volunteers and 20 with severe HG. There were no statistically significant differences between the maternal characteristics. The first trimester weight loss of ≥5 kg was significantly higher in the severe HG group (p < 0.001), while the control group had a significantly higher sunlight exposure ratio than the severe HG group (p = 0.021). The urine NTx levels were significantly higher in the severe HG group (39.22 ± 11.68NTx/Cre) than in the control group(32.89 ± 8.33NTx/Cre) (p = 0.028).The serum Ca, PTH, Na, K, BUN, and creatinine levels were similar between the groups (p = 0.738, p = 0.886, p = 0.841, p = 0.957, p = 0.892, and p = 0.824, respectively). In the severe HG group, the serum 25OHD3 levels were significantly lower than in the control group (p < 0.001).ConclusionsThe data from this study indicated that severe HG is associated with increased urine NTx levels. However, large-scale studies are required to understand the clinical significance of this finding, as well as the long-term consequences of elevated urine NTx levels and the underlying mechanisms.Trial registrationNCT02862496 Date of registration: 21/07/2016.

Prednisolone Effects on Urine Cross-Linked N-Telopeptides of Type I Collagen (Ntx) Diurnal Rhythms in Children.

Recently, methods for mimicking endogenous cortisol rhythms hereby potentially reducing the risk of systemic adverse effects of exogenous corticosteroids have been patented. Methods for sensitive detection of adverse effects on bone turnover of various doses, administration routes and regimens of exogenous corticosteroids have been patented. Urine cross-linked Ntelopeptides of Type I collagen (Ntx) have been established as a sensitive bone resorption marker and urine levels of Ntx have been found to exhibit a distinct diurnal rhythm. To assess whether the timing of administration of prednisolone affects the diurnal rhythm of Ntx in urine. Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I-IV were studied in an open randomized 2-periods cross-over trial, with a 1-day run in, and two 4-day periods of 5mg prednisolone in the morning and in the evening, respectively, separated by a 3-week washout period. At run in and on the last day of each treatment period, the first sample of urine was collected from 24.00 to 08.00h in the morning of the day of investigation. Thereafter, urine was collected in 4~hour intervals until 24.00 and in another 08.00h interval from 24.00 to 08.00h. Compared to run in and morning prednisolone treatment urine Ntx levels were suppressed from 24.00 to 8.00h during treatment with prednisolone in the evening (P < 0.01 for both comparisons) and no statistically significant circadian rhythm was observed. During morning prednisolone treatment Ntx trough and peak levels occurred from 16.00 to 20.00 and 24.00 to 08.00h, respectively, and the Ntx levels were significantly reduced from 12.00 to 20.00h as compared to run in (P < 0.005) and prednisolone treatment in the evening (P < 0.01). Depending on the time of administration, prednisolone interferes with diurnal rhythms in urine Ntx.

Tocotrienol supplementation suppressed bone resorption and oxidative stress in postmenopausal osteopenic women: a 12-week randomized double-blinded placebo-controlled trial.

Tocotrienols (TT) have been shown to benefit bone health in ovariectomized animals, a model of postmenopausal women. The purpose of this study was to evaluate the effect of 12-week TT supplementation on bone markers (serum bone-specific alkaline phosphatase (BALP), urine N-terminal telopeptide (NTX), serum soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), and serum osteoprotegerin (OPG)), urine calcium, and an oxidative stress biomarker (8-hydroxy-2'-deoxyguanosine (8-OHdG)) in postmenopausal women with osteopenia. Eighty-nine postmenopausal osteopenic women (59.7 ± 6.8year, BMI 28.7 ± 5.7kg/m2) were randomly assigned to three groups: (1) placebo (430mg olive oil/day), (2) low TT (430mg TT/day, 70% purity), and (3) high TT (860mg TT/day, 70% purity). TT, an extract from annatto seed with 70% purity, consisted of 90% delta-TT and 10% gamma-TT. Overnight fasting blood and urine samples were collected at baseline, 6, and 12weeks for biomarker analyses. Eighty-seven subjects completed the 12-week study. Relative to the placebo group, there were marginal decreases in serum BALP level in the TT-supplemented groups over the 12-week study period. Significant decreases in urine NTX levels, serum sRANKL, sRANKL/OPG ratio, and urine 8-OHdG concentrations and a significant increase in BALP/NTX ratio due to TT supplementation were observed. TT supplementation did not affect serum OPG concentrations or urine calcium levels throughout the study period. There were no significant differences in NTX level, BALP/NTX ratio, sRANKL level, and sRANKL/OPG ratio between low TT and high TT groups. Twelve-week annatto-extracted TT supplementation decreased bone resorption and improved bone turnover rate via suppressing bone remodeling regulators in postmenopausal women with osteopenia. Such osteoprotective TT's effects may be, in part, mediated by an inhibition of oxidative stress. ClinicalTrials.gov identifier: NCT02058420. Tocotrienols and bone health of postmenopausal women.

Minodronic acid suppresses gonadotropin-releasing hormone agonist-induced bone remodeling biomarkers: a retrospective pilot study

Background: Estrogen deprivation therapy for myoma/adenomyosis decreases bone mineral density and can only be applied in the short term, as temporizing measures in the premenopausal woman.Objective: To examine the effects of bisphosphonate minodronic acid on markers of bone turnover over a 6-month period in women receiving gonadotropin-releasing hormone agonist (GnRHa).Methods: We retrospectively analyzed the medical records of 19 premenopausal patients with myoma/adenomyosis, who received GnRHa (leuprolide acetate, 1.88 mg/month or buserelin acetate, 900 µg/day) for 6 months from January 2014 to December 2014. Eight patients concomitantly received minodronic acid 50 mg every month during GnRHa therapy, and 11 treated with GnRHa alone. To compare these data in a case-controlled study, we analyzed an age-matched group of seven (premature or natural) menopausal women treated with minodronic acid. The primary outcome was percent changes in bone turnover markers in urine at 6 months.Results: In menopausal women group, minodronic acid (50 mg once-monthly) for 6 months decreased urinary deoxypyridinoline (DPD) and cross-linked N-telopeptides of type 1 collagen (NTX). Women receiving a GnRHa had a significant increase in urinary DPD and TNX at 6 months while minodronic acid during GnRHa therapy improved urinary levels of DPD and NTX to near baseline.Conclusion: Minodronic acid treatment appears to be promising in women with secondary bone loss receiving GnRHa treatment.

Effect of minodronate on the speed of sound of the calcaneus in postmenopausal women with an increased risk of fractures: A clinical practice-based observational study

BackgroundWe previously reported that alendronate and risedronate reduce the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) by 44.9% and 34.7%, respectively, at 3 months after the start of treatment, and increase the speed of sound (SOS) of the calcaneus by 0.6% and 0.65%, respectively, at 12 months after the start of treatment in postmenopausal women with osteoporosis. The aim of the present clinical practice-based observational study was to examine the effect of treatment with minodronate for 12 months on the SOS of the calcaneus and on bone turnover markers in postmenopausal women with an increased risk of fractures. MethodsForty-two postmenopausal women with osteoporosis or osteopenia with a clinical risk factor for fractures who had been treated with minodronate for > 12 months were enrolled in the study. The SOS and bone turnover markers were monitored during treatment with minodronate for 12 months. ResultsCompared to their baseline values, the urinary levels of NTX at 3 months and the serum levels of alkaline phosphatase at 12 months were significantly decreased at 47.5% and 25.8%, respectively. At 12 months, the SOS increased modestly, but significantly, by 0.47%, compared to the baseline value. ConclusionThe present study confirmed that minodronate suppressed bone turnover and modestly increased the SOS of the calcaneus in postmenopausal women with an increased risk of fractures.

Urinary N telopeptide levels in predicting the anti-nociceptive responses of zoledronic acid and paclitaxel in a rat model of bone metastases.

The present study investigated the hypothesis that urinary levels of N telopeptide (NTx) can be used to predict the anti-nociceptive responses of zoledronic acid and paclitaxel on bone metastases in a rat model. Rats were implanted with intra-femur Walker 256 carcinoma cells or control solution, and were treated with either normal saline, zoledronic acid or paclitaxel on the 10th day following surgery. Mechanical allodynia was recorded and the urine collagen-crosslinked NTx values were measured prior to, and 7, 14 and 21 days following the injections. Bone sections and osteoclasts were stained on the 14th day (4 days post-injection). Furthermore, the mRNA and protein expression levels of c-fos in the spinal cord and acid-sensing ion channel 3 (ASIC3) in the dorsal root ganglion (DRG) were analyzed. The mechanical allodynia of rats was attenuated from day 14 in the zoledronic acid group and from day 21 in the paclitaxel group. A positive correlation was observed between the anti-nociceptive responses of zoledronic acid and paclitaxel, and the urinary levels of NTx (r=0.619; P<0.001). The mRNA levels of c-fos in the spinal cord and ASIC3 in the DRG in the zoledronic acid group were reduced 14 and 21 days after inoculation, and this reduction was observed in the paclitaxel group 21 days after inoculation. Low dose paclitaxel was observed to have a weaker anti-nociceptive effect on bone cancer pain, with a later-onset, compared with zoledronic acid. The results suggested that urinary levels of NTx may predict the anti-nociceptive responses of zoledronic acid and paclitaxel in a rat model of bone metastases.

Prospective Evaluation of Zoledronic Acid in the Treatment of Bone Metastases from Differentiated Thyroid Carcinoma.

The objectives of this study were to prospectively delineate the efficacy and safety of zoledronic acid for treating bone metastases (BM) from differentiated thyroid carcinoma (DTC), and to evaluate the relationships between levels of bone metabolic markers and occurrence of skeletal-related events (SREs). This was a prospective, single-arm, single-center study. Nineteen patients with BM from DTC were assigned to receive zoledronic acid therapy every 4-5 weeks. Imaging studies for sites of BM were conducted every 6 months, and levels of bone metabolic markers, including serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide of type I collagen (NTx), were assessed every 3 months. To evaluate the efficacy of zoledronic acid use, data of SREs were compared with those of 16 historical controls. SREs developed in eight patients (42 %), but metastatic spinal cord compression (MSCC) appeared in only one patient. Pain scores were ameliorated in five patients, but aggravated in six patients. Ten patients had stable disease, six showed progressive disease, and none showed partial or complete response during the observation period. Decreases in levels of bone metabolic markers were observed in ten patients for BAP and 15 for NTx. However, no significant correlations were identified between changes in bone metabolic marker levels and development of SREs. Zoledronic acid may offer a mainstay of multidisciplinary treatment for patients with BM for the purpose of reducing SREs. Levels of serum BAP and urinary NTx do not appear reliable as indicators of amelioration of BM symptoms.

Experience with alendronate treatment for 7 years among Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures.

A retrospective study was performed to evaluate the outcome of alendronate treatment for 7 years among Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures. Thirty-five Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures (mean age at baseline 58.2 years) who had been treated with alendronate for over 7 years in our outpatient clinic were analyzed. The lumbar spine or total hip bone mineral density (BMD) was measured using dual energy X-ray absorptiometry; the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) and the serum levels of alkaline phosphatase (ALP) were monitored; the incidence of fractures during the 7-year treatment period was then assessed. The urinary NTX and serum ALP levels decreased (-46.1% at 3 months and -21.1% at 7 years, respectively) and the lumbar spine and total hip BMD increased (+14.2 and +10.1% at 7 years, respectively), compared with the baseline values. Four patients (11.4%) experienced vertebral fractures, and one patient (2.9%) experienced a nonvertebral fracture. No serious adverse events were observed, including osteonecrosis of the jaw or atypical femoral fractures. These results suggested that alendronate suppressed bone turnover and increased the lumbar spine and total hip BMD from the baseline values over the course of the 7-year treatment period without causing any severe adverse events in Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures.

PO-0079 Urinary N-telopeptide Levels Are Not Associated With Vitamin D Status In Healthy Children

Background and aims Urinary levels of N-telopeptide (NTx) have been reported to be a sensitive and specific marker of bone resorption. This cross-sectional study determined the urinary levels of NTx among healthy children living in Calgary and explored their relationship with age, sex and vitamin D status. Methods We included healthy children 2 to 13 years of age who presented to the Alberta Children’s Hospital for elective surgery during a 12-month period. Data including the child’s weight, height, age, gender, ethnicity, dietary intake, vitamin intake, and physical activity were collected. Urinary NTx levels were measured with a commercially (Wampole Laboratories, Princeton) available competitive-inhibition enzyme-linked immunosorbent assay. Results Urinary NTx levels were available for 968 out of 1862 participants, of whom 605 (62.5%) were boys. The mean urinary NTx/Creatinine ratio was 605.4 nmol/mmol (SD 264.8, range 200–2985.1). We found that mean urinary NTx/creatinine excretion was higher in the younger children (2–5 years) compared to subsequent ages. There was no significant difference in urinary NTx levels between children with suboptimal vitamin D status (serum 25-hydroxyvitamin D Conclusions Higher urinary NTx levels were measured in our healthy paediatric participants compared to what has been reported in healthy adults. In healthy children, urinary NTx levels may not be a useful marker of increased bone turnover in face of suboptimal vitamin D status. Future research is needed to determine the effect of suboptimal vitamin D status on bone health in children.

Highlights of This Issue

Early identification of complex disease-, gene-, and drug-drug interactions and quantitative prediction of their impacts are of great importance to the rational development and optimal use of anticancer drugs. Li and colleagues illustrated the utility of in vitro-in vivo extrapolation and physiologically based pharmacokinetic modeling approach to assess interactions of veliparib, a potential chemosensitizer, with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment). The obtained quantitative information is useful in aiding decision-making regarding whether further clinical studies are needed to assess interactions and risks, and also in guiding dose optimization in response to complex drug interaction scenarios.Aminobisphosphonates (aBPs), such as zoledronate, prevent skeletal-related events in patients with multiple myeloma. However, the extended use of aBPs is associated with osteonecrosis of the jaw as a possible consequence of aBP oversuppression of bone-remodeling. Patel and colleagues studied urinary levels of NTX, a marker of bone resorption, in multiple myeloma patients whose disease was in remission. The authors found that NTX levels remained stable in the 6 months following cessation of aBPs in 28 of 29 patients. This study suggests that less frequent dosing of aBPs is feasible and may help minimize the risks of continued treatment with aBPs while maintaining its benefit.Chemotherapy for gastric cancer is often initially effective but resistance develops quickly. Yoon and colleagues examined a subset of CD44(+) gastric cancer cells with cancer stem cell properties including chemotherapy resistance and found the Hedgehog signaling pathway to be upregulated in these cells. Inhibition of the Hedgehog signaling pathway in these CD44(+) cells reversed chemotherapy resistance in vitro and in vivo. In a randomized clinical trial of chemotherapy with or without the Hedgehog inhibitor vismodegib for advanced gastric cancers, patients with high CD44 expressing tumors treated with chemotherapy plus vismodegib had improved outcomes.The FGFR gene rearrangements were identified in diverse cancers. To explore their prevalence and clinicopathologic characteristics in non-small cell lung cancers (NSCLCs), Wang and colleagues analyzed 1328 NSCLCs for FGFR1, FGFR2, and FGFR3 fusions using RT-PCR and described the clinicopathologic characteristics of patients with FGFR fusions. FGFR1/3 fusions occurred in 1.3% of patients with NSCLCs. FGFR fusions identified a distinct subset of NSCLC with a higher prevalence among smokers with squamous cell carcinoma and relative larger tumor (&gt; 3cm). FGFR is a druggable target and patients with FGFR fusions may benefit from FGFR targeted therapy which needs further clinical investigation.

Biomarkers of bone remodeling in multiple myeloma patients to tailor bisphosphonate therapy.

Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs.

Calorie restriction aggravated cortical and trabecular bone architecture in ovariectomy-induced estrogen-deficient rats

We hypothesized that calorie restriction (CR) and estrogen deficiency (ovariectomy [OVX]) would aggravate bone biomarkers and structural parameters in rats. Seven-week-old female Sprague-Dawley rats were randomized to sham-operated groups and fed either an ad libitum diet (SHAM-AL) or a CR diet (SHAM-CR); ovariectomy-operated groups were fed an ad libitum diet (OVX-AL) or a CR diet (OVX-CR). For 8 weeks, the OVX-AL and SHAM-AL groups were fed the same diet, whereas CR groups were fed a diet containing 50% fewer calories. Bone-related biomarkers and structural parameters (OC; deoxypyridinoline [DPD]; N-terminal telopeptide, NTx; architecture and mineralization; and microcomputed tomography images) were analyzed at the end of the experiment. The serum OC levels of calorie-restricted groups (SHAM-CR and OVX-CR) were significantly lower than those of the AL groups (SHAM-AL and OVX-AL) (P < .05). Urinary DPD levels of calorie-restricted and ovariectomized groups were higher than those of their counterparts (P < .05), whereas urinary NTx levels of calorie-restricted groups were higher than those of AL groups (P < .05). In regard to trabecular bone, the calorie-restricted and ovariectomized groups had lower values of bone volume to total volume, trabecular number, and bone mineral density, but higher values of trabecular separation than those of their counterparts (P < .05). Regarding cortical bone, the calorie-restricted groups had reduced values of bone volume, mean polar moment of inertia, and cortical thickness compared to the AL groups (P < .05). In conclusion, severe CR with or without OVX during the growth period in rats is equally detrimental to bone; CR has detrimental effects on trabecular and cortical bone; and estrogen deficiency only had an effect on trabecular bone.

Effects of alendronate or alfacalcidol on bone metabolic indices and bone mineral density in patients with ophthalmologic disease treated with glucocorticoid

Objectives. Glucocorticoid (GC) is usually used for the treatment of systemic inflammatory diseases. We performed the prospective study to clarify the effects of alendronate or alfacalcidol on bone metabolic indices and bone mineral density (BMD) in 90 patients treated with GC for ophthalmologic diseases without systemic disorders for 12 months.Methods. BMD was measured with dual-energy X-ray absorptiometry. Serum bone-specific alkaline phosphatase (BAP) and urinary Type I collagen cross-linked N-telopeptide (NTx) were measured as bone metabolic indices.Results. BMD values in the alendronate group were significantly higher than those in the alfacalcidol group during 12 months. Alendronate significantly reduced urinary NTX levels from the baseline during 12 months, although alfacalcidol did not affect them. Serum BAP levels in the alendronate group were significantly lower than those in the alfacalcidol group during 9 months. The effects of alendronate on BMD and NTx in male patients seemed to be somewhat potent compared with those in female patients.Conclusions. Alendronate is effective to prevent BMD loss and bone resorption induced by GC treatment in patients with ophthalmic diseases without systemic disorders. There might be sex differences in the potency of alendronate effects.

N-telopeptide of type I collagen (NTX) dynamics over one year of determinations in patients with breast cancer (BC) with bone metastases (BM): Predictive factors of outcome.

9634 Background: The bone resorption marker NTX at baseline is a prognostic marker in BC patients with BM treated with zoledronic acid (ZOL), Coleman RE, JCO 2005. We investigate how the response of urinary NTX levels during ZOL therapy is related to patient outcome and disease characteristics. Methods: Consecutive BC patients with BM were prospectively included if they received monthly intravenous ZOL. Urinary NTX was determined at baseline and at following 1, 3, 6, 9 and 12 months from the initial ZOL treatment. NTX levels were considered elevated if &gt; 50 nmol/mmol creatinine. The NTX changes were compared with patient and disease characteristics. Relative risks for negative clinical outcomes were estimated with Cox regression models. Results: Seventy-one BC patients with BM, mean aged 61.4 (29-87), were included. Mean survival was 34.1 months (3-131), with 21 patients alive after the last follow up (median 29 months). Thirty-nine patients also had extraskeletal metastases (BM-E+). Totally 329 urinary NTX samples were evaluated. At baseline, mean NTX was 153.0 (15.4 – 700.7) and 78.9% had elevated levels. Mean baseline NTX increased with age: 71.2 (&lt;40); 139.3 (50-59); 241.8 (70-79). Among patients with normal NTX at 3 months, 89.5% continued to show normal NTX at 12 months. After ZOL treatments, 46.9%, 54.7%, and 61.0% of patients had normal NTX at 3, 6 and 12 months, respectively. NTX variance (1-12 months) was higher for BM-E+ patients compared with BM-only patients, p&lt;0.001. Risk factor of death for patients with persistent elevated NTX at 3 months was 1.74 (p=0.074). Age and BM-E+ were also associated with risk of death. There was a trend to shorter survival in BC-E+ patients (p=0.056). Majority of patients (88.2%) with longer survival (&gt; 36 months) and younger (age &lt; 60) received endocrine therapy. Conclusions: Early (3 months) urinary NTX normalization to ZOL correlates with long-term NTX normalization and survival. BC-E+ patients have a reduced NTX normalization rate compared to BM-only patients and may deserve further investigation for a more adequate schedule of bone-targeting agents.

Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Abstract 3965 Background:Aminobisphosphonates (aBP) are standard of care for myeloma-related bone disease and are recommended every 3–4 weeks. Multiple myeloma patients may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures secondary to altered bone remodeling due to long-term aBP therapy. Monthly dosing of aBP is based on early studies that documented the suppression of N-telopeptide (NTX), a marker of bone resorption, for 4–8 weeks following a single dose of aBP. However, it is unclear whether NTX or other bone biomarkers are predictive of skeletal related events (SRE) or what the impact of cessation of aBP therapy has on bone remodeling. Methods:We studied markers of bone turnover after a single dose of zoledronic acid in myeloma patients in remission (NCT00577642). All patients had received 8–12 doses of aBP (pamidronate/zoledronic acid) prior to study inclusion. Patients were not receiving active anti-myeloma therapy besides maintenance therapy. Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronic acid on study. A secondary objective was the identification and correlation of other markers of bone remodeling with NTX changes. High throughput cytokine arrays of validated and potential surrogate markers of bone remodeling were performed. Bone marrow biopsies at start and end of protocol during which time aBPs were not administered were performed. Patients were removed from study if NTX crossed a threshold value (50 nMol), based on correlation of NTX levels with bone-related morbidity and mortality. Results:Twenty-nine patients were enrolled in a 6-month period. Cytokine array data is available in 28 patients. All patients had suppressed NTX levels, except one patient who had an increase in NTX levels associated with a SRE and disease progression. To identify other surrogate as yet unexplored cytokines that may serve as better markers in addition to NTX to monitor aBP activity, thirty cytokines were curated from the literature based on their possible role in bone remodeling and tested using custom designed cytokine arrays. Positive hits were confirmed by ELISA. GDF-15, which correlates with poor prognosis in myeloma and is thought to be produced by bone marrow mesenchymal stem cells, decreased in 24 of 28 patients (two-sided paired T test, p<0.001). However, decorin, a proteoglycan produced by osteoblasts that seems to have anti-myeloma properties based on knockdown studies, decreased in 20 of 28 patients at 6 months as compared to beginning of study (two-sided paired T test, p<0.001). In addition, there was evidence that there is some recovery of osteoblast function with cessation of aBP, with increased osteopontin and osteoprotegerin levels in at least half of the patients. Although these results were not significant in aggregate, when complemented with ELISA results of bone-specific alkaline phosphatase showing an increase in 18 of 28 patients (two-sided paired T test, p<0.001), they signify that oversuppression of osteoblasts by long-term aBP may be reversible. Effects on osteoclasts and osteoblasts are being confirmed by immunohistochemistry on BM biopsies. Conclusion:Our data suggest that suppressed NTX levels are predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP is reversible in myeloma. Importantly, the role of other surrogates such as decorin and GDF-15 need further validation and are the subject of ongoing studies. Taken together, this evidence may provide rationale for less frequent aBP dosing in multiple myeloma patients to help lower the incidence of long term toxicities such as ONJ and stress fractures, by allowing limited recovery of bone remodeling without adverse effects on multiple myeloma progression. Disclosures:Richardson:Novartis: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Ghobrial:Bristol Myers Squibb: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other; Novartis: Advisory Board Other. Schlossman:Celgene: Membership on an entity’s Board of Directors or advisory committees. Anderson:Onyx: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees. Raje:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding.