Usefulness of bone turnover markers as predictors of mortality risk, disease progression and skeletal-related events appearance in patients with prostate cancer with bone metastases following treatment with zoledronic acid: TUGAMO study.
ABSTRACT: BACKGROUND: Owing to the limited validity of clinical data on the treatment of prostate cancer (PCa) and bone metastases, biochemical markers are a promising tool for predicting survival, disease progression and skeletal-related events (SREs) in these patients. The aim of this study was to evaluate the predictive capacity of biochemical markers of bone turnover for mortality risk, disease progression and SREs in patients with PCa and bone metastases undergoing treatment with zoledronic acid (ZA). METHODS: This was an observational, prospective and multicenter study in which ninety-eight patients were included. Patients were treated with ZA (4 mg every 4 weeks for 18 months). Data were collected at baseline and 3, 6, 9, 12, 15 and 18 months after the beginning of treatment. Serum levels of bone alkaline phosphtase (BALP), aminoterminal propeptide of procollagen type I (P1NP) and beta-isomer of carboxiterminal telopeptide of collagen I (β-CTX) were analysed at all points in the study. Data on disease progression, SREs development and survival were recorded. RESULTS: Cox regression models with clinical data and bone markers showed that the levels of the three markers studied were predictive of survival time, with β-CTX being especially powerful, in which a lack of normalisation in visit 1 (3 months after the beginning of treatment) showed a 6.3-times more risk for death than in normalised patients. Levels of these markers were also predictive for SREs, although in this case BALP and P1NP proved to be better predictors. We did not find any relationship between bone markers and disease progression. CONCLUSION: In patients with PCa and bone metastases treated with ZA, β-CTX and P1NP can be considered suitable predictors for mortality risk, while BALP and P1NP are appropriate for SREs. The levels of these biomarkers 3 months after the beginning of treatment are especially important.
Project description:Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomized to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline and months 4 and 12; BMD at the spine (dual-energy X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared with the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (?CTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p ? 0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and ?CTX at month 4 predicted decrease in hip BMD at month 12, whereas increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months.
Project description:Observational studies suggested a link between bone disease and left ventricular (LV) dysfunction that may be pronounced in hyperparathyroid conditions. We therefore aimed to test the hypothesis that circulating markers of bone turnover correlate with LV function in a cohort of patients with primary hyperparathyroidism (pHPT). Cross-sectional data of 155 subjects with pHPT were analyzed who participated in the "Eplerenone in Primary Hyperparathyroidism" (EPATH) Trial. Multivariate linear regression analyses with LV ejection fraction (LVEF, systolic function) or peak early transmitral filling velocity (e', diastolic function) as dependent variables and N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin (OC), bone-specific alkaline phosphatase (BALP), or beta-crosslaps (CTX) as the respective independent variable were performed. Analyses were additionally adjusted for plasma parathyroid hormone, plasma calcium, age, sex, HbA1c, body mass index, mean 24-hours systolic blood pressure, smoking status, estimated glomerular filtration rate, antihypertensive treatment, osteoporosis treatment, 25-hydroxy vitamin D and N-terminal pro-brain B-type natriuretic peptide. Independent relationships were observed between P1NP and LVEF (adjusted ?-coefficient = 0.201, P = 0.035) and e' (? = 0.188, P = 0.042), respectively. OC (? = 0.192, P = 0.039) and BALP (? = 0.198, P = 0.030) were each independently related with e'. CTX showed no correlations with LVEF or e'. In conclusion, high bone formation markers were independently and paradoxically related with better LV diastolic and, partly, better systolic function, in the setting of pHPT. Potentially cardio-protective properties of stimulated bone formation in the context of hyperparathyroidism should be explored in future studies.
Project description:Bone turnover markers (BTMs) are used to evaluate bone health together with bone mineral density and fracture assessment. Vitamin D supplementation is widely used to prevent and treat musculoskeletal diseases but existing data on vitamin D effects on markers of bone resorption and formation are inconsistent. We therefore examined the effects of vitamin D supplementation on bone-specific alkaline phosphatase (bALP), osteocalcin (OC), C-terminal telopeptide (CTX), and procollagen type 1 N-terminal propeptide (P1NP). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial, a single-center, double-blind, randomized, placebo-controlled trial (RCT) performed at the Medical University of Graz, Austria (2011-2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D (25[OH]D) levels <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for eight weeks. One hundred ninety-seven participants (60.2 ± 11.1 years; 47% women) were included in this analysis. Vitamin D had no significant effect on bALP (mean treatment effect (MTE) 0.013, 95% CI -0.029 to 0.056 µg/L; p = 0.533), CTX (MTE 0.024, 95% CI -0.163 to 0.210 ng/mL, p = 0.802), OC (MTE 0.020, 95% CI -0.062 to 0.103 ng/mL, p = 0.626), or P1NP (MTE -0.021, 95% CI -0.099 to 0.057 ng/mL, p = 0.597). Analyzing patients with 25(OH)D levels <50 nmol/L separately (n = 74) left results largely unchanged. In hypertensive patients with low 25(OH)D levels, we observed no significant effect of vitamin D supplementation for eight weeks on BTMs.
Project description:BACKGROUND:Skeletal-related events (SREs), common sequelae of metastatic cancer, are reduced by bisphosphonates. In this study, it was postulated that radiopharmaceuticals, added to bisphosphonates, could further decrease the incidence of SREs. METHODS:NRG Oncology RTOG 0517 randomized patients with breast, lung, and prostate cancer and blastic bone metastases to either zoledronic acid (ZA) alone or ZA plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life (QOL), pain control, overall survival (OS), and toxicity. RESULTS:261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued between July 2006 and February 2011. The study closed early due to a lower than expected rate of SREs. 52 (42%) patients in the ZA arm and 49 (40%) in the radiopharmaceutical arm experienced an SRE. Median time free of SREs was 29.9 and 27.4 months, respectively (p?=?0.84). Median OS in the ZA arm and radiopharmaceutical arms was 32.1 and 26.9 months, respectively (p?=?0.37). Cox proportional hazards regression model showed that primary disease site (lung) and number of bone metastases (>?2) had a negative impact on OS (p?<?0.0001, p?=?0.01, respectively). The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at 1 month based on BPI worst score (p?=?0.02). No other group differences were noted for QOL or toxicity. CONCLUSION:The addition of radiopharmaceuticals to bisphosphonates did not alter time to SREs or OS for patients with breast, lung, prostate cancers and blastic bone metastases, although it was associated with significant pain reduction at 1 month. CLINICAL TRIAL REGISTRY:This protocol (RTOG 0517) is registered with ClinicalTrials.gov (NCT00365105), and may be viewed online at http://www.clinicaltrials.gov/ct2/show/NCT00365105?term=RTOG+0517&rank=1 .
Project description:BACKGROUND: Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL). METHODS: This observational, prospective, and multicenter study analysed BTM and clinical outcome in these patients. Serum levels of bone alkaline phosphatase (BALP), procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxy-terminal telopeptide of type I collagen (β-CTX) were analysed. RESULTS: Patients with RCC who died or progressed had higher baseline β-CTX levels and those who experienced SRE during follow-up showed high baseline BALP levels. In BC, a poor rate of survival was related with high baseline β-CTX and BALP levels, and new SRE with increased PINP levels. Cox univariate analysis showed that β-CTX levels were associated with higher mortality and disease progression in RCC and higher mortality in BC. Bone alkaline phosphatase was associated with increased risk of premature SRE appearance in RCC and death in BC. CONCLUSION: Beta-isomer of carboxy-terminal telopeptide of type I collagen and BALP can be considered a complementary tool for prediction of clinical outcomes in patients with BC and RCC with BM treated with ZOL.
Project description:OBJECTIVES:To assess cost implications per patient, per year, and to predict the potential annual budget impact when patients with bone metastases secondary to solid tumours at risk of skeletal-related events (SREs) transition from zoledronic acid (ZA; 4 mg every 3-4 weeks) to denosumab (120 mg every 4 weeks) in Austria, Sweden and Switzerland. METHODS:Country specific costs for medication and administration, patient management and SREs (defined as pathologic fracture, radiation to bone, surgery to bone and spinal cord compression) were assessed over a 1-year time horizon. Drug administration and patient management costs were taken from available public sources. SRE costs were based on local unit costs applied to country specific healthcare resources obtained from a multinational retrospective chart review study. Due to lack of real world data for the included countries, SRE rates were derived from phase III clinical trials in patients with advanced cancer and bone metastases. These trials demonstrated that denosumab was superior to ZA in the reduction of SREs. RESULTS:Estimated total annual cost savings for each patient transitioned from ZA to denosumab varied by country and cancer type, ranging from €1583 to €2375 in Austria, from €1980 to €2319 in Sweden (9.1 SEK/€) and from €3408 to €3857 in Switzerland (1.2 CHF/€). Cost savings were mainly driven by the lower SRE related costs and lower administration costs of denosumab compared with ZA. CONCLUSIONS:Denosumab offers superior efficacy compared with ZA in patients with solid tumours and bone metastases. Cost savings are predicted in the Austrian, Swedish and Swiss healthcare systems following treatment transition from ZA to denosumab.
Project description:Background:Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis. Methods:Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided. Results:When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI?=?0.51 to 0.62), and 1-CTP of 0.57 (95% CI?=?0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid. Conclusions:Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study.
Project description:<h4>Background</h4>Biochemical markers of bone turnover are lower in patients with type 2 diabetes, which may be explained by genetic variants being associated with type 2 diabetes and bone turnover as well as environmental factors. We hypothesized that bone turnover markers associate with and predict changes in glucose homeostasis after control for genetics and shared environment.<h4>Methods</h4>1071 healthy, non-diabetic (at baseline, 1997-2000) adult mono- and dizygotic twins participating in the prospective study GEMINAKAR were reassessed between 2010 and 2012 with clinical evaluation, biochemical tests and oral glucose tolerance test. Fasting bone turnover markers (CTX, P1NP and osteocalcin) were measured. The association between bone turnover, glucose homeostasis and the ability of bone turnover markers to predict changes in glucose homeostasis were assessed in cross-sectional and longitudinal analyses. Analyses were performed both at an individual level and adjusted for shared environmental and genetic factors.<h4>Results</h4>Glucose levels increased with age, and 33 (3%) participants had developed type 2 diabetes at follow-up. In women, bone turnover markers increased with age, whereas for men only osteocalcin increased with age. Bone turnover markers were not associated with fasting glucose, insulin, or HOMA-IR at baseline or follow-up before or after adjustment for age, sex, BMI, smoking, and use of medication at baseline. Variation in bone turnover markers was mainly explained by unique environmental factors, 70%, 70% and 55% for CTX, P1NP and osteocalcin, respectively, whereas additive genetic factors explained 7%, 13% and 45% of the variation in CTX, P1NP and osteocalcin.<h4>Conclusions</h4>Bone turnover markers were not associated with baseline plasma glucose levels and did not predict changes in glucose homeostasis. Variation in bone turnover markers is mainly explained by environmental factors, however, compared to CTX and P1NP, genetic factors have a larger impact on osteocalcin levels.
Project description:Objectives: To investigate diet-exercise interactions related to bone markers in elite endurance athletes after a 3.5-week ketogenic low-carbohydrate, high-fat (LCHF) diet and subsequent restoration of carbohydrate (CHO) feeding. Methods: World-class race walkers (25 male, 5 female) completed 3.5-weeks of energy-matched (220 kJ·kg·d-1) high CHO (HCHO; 8.6 g·kg·d-1 CHO, 2.1 g·kg·d-1 protein, 1.2 g·kg·d-1 fat) or LCHF (0.5 g·kg·d-1 CHO, 2.1 g·kg·d-1 protein, 75-80% of energy from fat) diet followed by acute CHO restoration. Serum markers of bone breakdown (cross-linked C-terminal telopeptide of type I collagen, CTX), formation (procollagen 1 N-terminal propeptide, P1NP) and metabolism (osteocalcin, OC) were assessed at rest (fasting and 2 h post meal) and after exercise (0 and 3 h) at Baseline, after the 3.5-week intervention (Adaptation) and after acute CHO feeding (Restoration). Results: After Adaptation, LCHF increased fasting CTX concentrations above Baseline (p = 0.007, Cohen's d = 0.69), while P1NP (p < 0.001, d = 0.99) and OC (p < 0.001, d = 1.39) levels decreased. Post-exercise, LCHF increased CTX concentrations above Baseline (p = 0.001, d = 1.67) and above HCHO (p < 0.001, d = 0.62), while P1NP (p < 0.001, d = 0.85) and OC concentrations decreased (p < 0.001, d = 0.99) during exercise. Exercise-related area under curve (AUC) for CTX was increased by LCHF after Adaptation (p = 0.001, d = 1.52), with decreases in P1NP (p < 0.001, d = 1.27) and OC (p < 0.001, d = 2.0). CHO restoration recovered post-exercise CTX and CTX exercise-related AUC, while concentrations and exercise-related AUC for P1NP and OC remained suppressed for LCHF (p = 1.000 compared to Adaptation). Conclusion: Markers of bone modeling/remodeling were impaired after short-term LCHF diet, and only a marker of resorption recovered after acute CHO restoration. Long-term studies of the effects of LCHF on bone health are warranted.
Project description:Phenylalanine hydroxylase (PAH) deficiency is a genetic disorder characterized by deficiency of the PAH enzyme. Patients follow a phenylalanine-restricted diet low in intact protein, and must consume synthetic medical food (MF) to supply phenylalanine-free protein. We assessed relationships between dietary intake and nutrient source (food or MF) on bone mineral density (BMD) and bone turnover markers (BTM) in PAH deficiency. Blood from 44 fasted females 11-52 years of age was analyzed for plasma phenylalanine, serum BTM [CTx (resorption), P1NP (formation)], vitamin D, and parathyroid hormone (PTH). BTM ratios were calculated to assess resorption relative to formation (CTx/P1NP). Dual energy X-ray absorptiometry measured total BMD and age-matched Z-scores. Three-day food records were analyzed for total nutrient intake, nutrients by source (food, MF), and compliance with MF prescription. Spearman's partial coefficients (adjusted for age, BMI, energy intake, blood phenylalanine) assessed correlations. All had normal BMD for age (Z-score >-2). Sixty-four percent had high resorption and normal formation indicating uncoupled bone turnover. CTx/P1NP was positively associated with food phenylalanine (r 2 = 0.39; p-value = 0.017), energy (r 2 = 0.41; p-value = 0.011) and zinc (r 2 = 0.41; p-value = 0.014). CTx/P1NP was negatively associated with MF fat (r 2 = -0.44; p-value = 0.008), MF compliance (r 2 = -0.34; p-value = 0.056), and positively with food sodium (r 2 = 0.43; p-value = 0.014). CTx/P1NP decreased significantly with age (p-value = 0.002) and higher PTH (p-value = 0.0002). Phenylalanine was not correlated with any bone indicator. Females with PAH deficiency had normal BMD but elevated BTM, particularly resorption. More favorable ratios were associated with nutrients from MF and compliance. Younger females had less favorable BTM ratios. Promoting micronutrient intake through compliance with MF may impact bone metabolism in patients with PAH deficiency. SYNOPSIS:Bone mineral density was normal in 44 females with PAH deficiency; however, bone turnover markers suggested uncoupling of bone resorption and formation, particularly in younger patients. Adequate nutrient intake from medical food and overall medical food compliance may positively impact bone turnover.