Baseline Bone Turnover Markers Research Articles

Randomized phase II placebo-controlled trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone receptor-positive metastatic breast cancer (MBC): OCOG Zamboney study—NCT00811369.

574 Background: Biomarkers of bone turnover, including urine N-telopeptide (uNTx) and serum C-telopeptide (sCTx) reflect tumor-related bone breakdown and have been used as surrogate measures of response to therapy in trials. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases (BM). We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in patients with BM. Methods: Postmenopausal patients with bone only, or bone predominant, hormone receptor positive MBC were randomised to F (500mg IM day 1, 14, 28, then monthly) with either vandetanib (100mg PO OD) (FV) or placebo (FP) until progression. The primary objective was uNTx response (>30% reduction from baseline). uNTx was collected at baseline, weekly to wk 4, at wk 12 and then every 12 wks. Secondary objectives included PFS, OS, RECIST response, pain and toxicity. Results: 61 patients were allocated to FV and 68 to FP. Median age was 59. 18% had received 1 prior chemotherapy regime and 73% prior endocrine therapy for MBC. uNTx response (n=124 pts) was 64% for FV vs. 52% for FP (p=0.20). No difference was detected between groups for median PFS; 6 months for FV vs. 4.8 months for FP, HR=0.93 (95% CI: 0.64 to 1.36). 16 patients died in FV arm vs. 21 in the FP arm, HR=0.71 (95% CI: 0.37 to 1.36). For those patients with measurable disease, clinical benefit rates were 41% and 43%, respectively, p=1.00. Serious adverse events were similar, 3.3% for FV vs. 5.9% for FP. Elevated baseline uNTx (>65 nM BCE/mmol Cr) was prognostic for PFS, HR=1.62 (95% CI: 1.08 to 2.43 and for mortality, HR= 2.4 (95% CI: 1.2 to 4.6). In an exploratory analysis uNTx was predictive of responsiveness to FV for PFS, HR=0.60 when uNTx >65 vs. HR=1.37 when uNTx <65, P = 0.025 for interaction. Conclusions: The addition of vandetanib to F did not improve biomarker response, PFS or OS compared to F alone in patients with bone predominant disease. Exploratory analyses confirmed that baseline bone turnover markers are prognostic for PFS and OS. Clinical trial information: NCT00811369.

Assessing the effect of baseline status of serum bone turnover markers and vitamin D levels on efficacy of teriparatide 20 μg/day administered subcutaneously in Japanese patients with osteoporosis

In this previously reported multicenter study, teriparatide 20μg/day was administered to elderly Japanese subjects (93% female; median age 70years) with osteoporosis and at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled period, which was followed by a 12month treatment period in which all subjects received open-label teriparatide. Subjects were randomized 2:1 to teriparatide versus placebo (teriparatide n=137, placebo-teriparatide n=70). This was an exploratory analysis to determine whether the baseline status of serum bone turnover markers (BTMs) and vitamin D levels affect the efficacy of teriparatide at 20μg/day. The BTMs included were type I procollagen N-terminal pro-peptide (P1NP) and type I collagen cross-linked C-telopeptide (CTX). Changes in BMD were analyzed by subgroups: (1) tertile subgroups of BTM; (2) BTM determined by the upper limit of normal; and (3) level of vitamin D. Teriparatide increased lumbar spine BMD in all subgroups by 10% or more through 24months. Subgroups with higher baseline BTM levels had greater mean percent changes of lumbar spine BMD through 24months. The baseline status of vitamin D sufficiency did not impact the mean percent change of lumbar spine BMD through 24months. Results of this study suggest that clinically significant increases in BMD can be achieved in patients receiving teriparatide regardless of baseline BTM or vitamin D levels. Additionally, when vitamin D is coadministered, vitamin D insufficiency would not be expected to affect the overall efficacy of teriparatide.

Bone resorption and fracture across the menopausal transition: the Study of Women's Health Across the Nation.

Bone turnover markers (BTMs) predict fracture in older women, whereas data on younger women are lacking. To test the hypothesis that BTMs measured before and after menopause predict fracture risk, we performed a cohort study of 2,305 women. Women attended up to nine clinic visits for an average of 7.6 ± 1.6 years; all were aged 42 to 52 years and were premenopausal or early perimenopausal at baseline. Incident fractures were self-reported. Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen (NTX) were measured at baseline. NTX was measured at each annual follow-up. Interval-censored survival models or generalized estimating equations were used to test whether baseline BTMs and changes in NTX, respectively, were associated with fracture risk. Hazard ratios (HRs) or odds ratios were calculated with 95% CIs. Women who experienced fractures (n = 184) had about a 10% higher baseline median NTX (34.4 vs 31.5 nanomoles of bone collagen equivalents per liter per nanomole of creatinine per liter; P = 0.001), but there was no difference in osteocalcin. A 1-SD decrease in lumbar spine bone mineral density (BMD) measured premenopausally was associated with a higher fracture risk during menopause (HR, 1.50; 95% CI, 1.28-1.68). Women with a baseline NTX greater than the median had a 45% higher risk of fracture, multivariable-adjusted (HR, 1.46; 95% CI, 1.05-2.26). The HR of fracture among women with both the lowest spine BMD (quartile 1) and the highest NTX (quartile 4) at baseline was 2.87 (95% CI, 1.61-6.01), compared with women with lower NTX and higher BMD. Women whose NTX increased more than the median had a higher risk of fracture (odds ratio, 1.51; 95% CI, 1.08-2.10). Women who had baseline NTX greater than the median experienced greater loss of spine and hip BMD. A higher urinary NTX excretion measured before menopause and across menopause is associated with a higher risk of fracture. Our results are consistent with the pathophysiology of transmenopausal changes in bone strength.

945 - Bone Turnover Markers and Potential Correlation with Outcomes in Patients with Genitourinary Cancer (PROSTATE) and Bone Metastasis (RESULTS OF TUGAMO STUDY)

ABSTRACT Background Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal related events (SRE), disease progression and death. The aim of this study was to determine the possible correlation between BTM, disease progression, SREs and death in patients with genitourinary cancer and bone metastases (BM) treated with zoledronic acid (ZA). Methods Observational, prospective, multicenter study. Patients with genitourinary cancer (prostate, renal, bladder) and BM were included. BTM determined were: carboxiterminal telopeptide of type I collagen (β-CTX) and bone specific alkaline phosphatase (BALP) by ELISA (immunoenzymatic assay, IDS UK), and aminoterminal propeptide of type I collagen (P1NP) by automatised assays (Elecsys, Roche). All BTM were determined at baseline (V0) and every 3 mo of treatment until Month 18 (V6). All patients started treatment with ZA 4 mg IV every 3-4 weeks at the beginning of the study. Results Data of 168 patients with genitourinary cancer were analyzed. In this work data of prostate cancer patients (n = 95) are presented. Population basal characteristics [35 new, without previous treatment (N) / 60 pre-treated, with anti-hormonal treatment (P)]: mean age (years): 72.1; median time from tumor diagnosis (months): 7.6 (N) / 11.6 (P); ECOG 0-1: 90% (N) / 87.5% (P). Patients with pathologic baseline levels were: 47.1% β-CTX, 64.7% BALP and 57.1% P1NP (N) and 48.3% β-CTX, 80.7% BALP and 60% P1NP (P). After 6 mo.: 28%, 48% and 32% (N) and 32%, 59.4% and 31.3% (P) presented pathologic values of β-CTX, BALP and P1NP respectively. Normalized levels remained steady throughout 18 mo follow-up. Reductions from baseline to month 3 in BALP levels correlated with lower risk of death (p = 0.0219) (Cox regression analysis). Conclusions Elevation of baseline BTM levels is frequently present in advanced prostate cancer with bone metastasis. Addition of AZ to standard systemic therapy reduces BTM levels, even though in those highly hormone sensitive ones. A significant association was observed between elevated levels of BALP and death throughout follow-up. Disclosure All authors have declared no conflicts of interest.

805P - Bone Turnover Markers and Potential Correlation with Outcomes in Patients with Genitourinary Cancer (Renal and Bladder) and Bone Metastasis (Results of the Tugamo Study)

ABSTRACT Background Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal related events (SRE), disease progression and death. The aim of the study was to determine the possible correlation between BTM, disease progression, SREs and death in patients with genitourinary cancer and bone metastases (BM) treated with zoledronic acid (ZA). Methods Observational, prospective, multicenter study. Patients with genitourinary cancer (prostate, renal, bladder) and BM were included. BTM determined were: carboxiterminal telopeptide of type I collagen (β-CTX) and bone specific alkaline phosphatase (BALP) by ELISA (immunoenzymatic assay, IDS UK), and aminoterminal propeptide of type I collagen (P1NP) by automatised assays (Elecsys, Roche). All BTM were determined at baseline (V0) and every 3 mo of treatment until Month 18 (V6). All patients started treatment with ZA 4 mg IV every 3–4 weeks at the beginning of the study. Results Data of 168 patients with genitourinary cancer were analyzed. In this work data of renal (RC) (n = 39) and bladder (BC) (n = 34) cancer patients are presented. Population basal characteristics: mean age (years): 65.1 (RC) / 64.4 (BC); median time from tumor diagnosis to detection of BM (months): 6.2 (RC) / 2.4 (BC); previous SRE: 56.4% (RC) / 50% (BC). Patients with pathologic baseline levels were: 47.4% β-CTX, 59% BALP and 31% P1NP (RC) and 71.9% β-CTX, 76.5% BALP and 81.3% P1NP (BC). After 6 mo: 0%, 21.1% and 26.7% (BC) and 0%, 18.2% and 10% (RC) presented pathologic levels of β-CTX, BALP and P1NP, respectively. Normalized levels remained steady throughout 18 mo follow-up. Reductions from baseline to Month 3 in s-CTX levels correlated with lower risk of progression (p = 0.0084) and death (p = 0.0232) (RC) / and death (p = 0.0189) (BC) (Cox regression analysis). Conclusions Elevation of baseline BTM levels is frequently present in advanced genitourinary cancer with bone metastasis. Addition of ZA to standard systemic therapy reduces BTM levels. A significant association was observed between elevated levels of s-CTX and disease progression and death (renal) and death (bladder) throughout follow-up. Disclosure All authors have declared no conflicts of interest.

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), and procollagen-1 N-terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double-blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (< 70 years versus ≥ 70 years), prior duration of ADT (≤ 6 months versus > 6 months), and baseline BTM (≤ median versus > median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was -90% in the denosumab group and -3% in the placebo group (p < 0.0001). The median change in TRAP-5b levels at month 1 was -55% in the denosumab group and -3% in the placebo group (p < 0.0001). The maximal median change in P1NP was -64% in the denosumab group and -11% in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously.

Bone turnover markers and prediction of fracture: A prospective follow-up study of 1040 elderly women for a mean of 9 years

Osteoporosis is characterized by compromised bone mass and strength, predisposing to an increased risk of fracture. Increased bone metabolism has been suggested to be a risk factor for fracture. The aim of this study was to evaluate whether baseline bone turnover markers are associated with long-term incidence of fracture in a population-based sample of 1040 women who were 75 years old (Malmö OPRA study). Seven bone markers (S-TRACP5b, S-CTX-I, S-OC[1-49], S-TotalOC, S-cOC, S-boneALP, and urinary osteocalcin) were measured at baseline and 1-year follow-up visit. During the mean follow-up of 9.0 years (range 7.4-10.9), 363 women sustained at least one fracture of any type, including 116 hip fractures and 103 clinical vertebral fractures. High S-TRACP5b and S-CTX-I levels were associated with increased risk of any fracture with hazard ratios [HRs (95% confidence interval)] of 1.16 (1.04-1.29) and 1.13 (1.01-1.27) per SD increase, respectively. They also were associated with increased risk of clinical vertebral fracture with HRs of 1.22 (1.01-1.48) and 1.32 (1.05-1.67), respectively. Markers were not associated with risk for hip fracture. Results were similar when we used resorption markers, including urinary osteocalcin, measured at the 1-year visit or an average of the two measurements. The HRs were highest for any fracture in the beginning of the follow-up period, 2.5 years from baseline. For vertebral fractures, the association was more pronounced and lasted for a longer period of time, at least for 5 years. In conclusion, elevated levels of S-TRACP5b, S-CTX-I, and urinary osteocalcin are associated with increased fracture risk for up to a decade in elderly women.

Response to Comparison of Teriparatide and Strontium Ranelate in Postmenopausal Women With Osteoporosis

Response to Comparison of Teriparatide and Strontium Ranelate in Postmenopausal Women With Osteoporosis

Relationship between baseline bone turnover marker levels and percent change in BMD at month 12 in postmenopausal women transitioned to denosumab or continuing on long-term alendronate therapy

the most frequent side effects (84.21%). First visit before age 60 years ensures a better adherence during the FU (p=0.018). Co-morbidities reduce adherence (p=0.047). Weekly bisphosponates absuntion presents better compliance rates than daily (p=0.005). Patients with history of fractures have better adherence (p<0.001). Adherence results higher since the first year post-fracture (p=0.048) and remain higher during FU (p=0.004). Dividing population in adherent and non-adherent at the 85% MPR cut-off results that non-adherent have an RR=1.75 of fracture. Considering the 3 periods of FU, adherence seems to increase over time (84.53% – 87,64% – 91.19%; p=0.025) Major determinants of adherence already described in clinical trials and relationship between adherence and fracture risk are confirmed in this real life study. An adherence rate increase is also detected with fractures history (more motivation) and in patients in therapy from many years. Conflict of interest: None declared.

Prediction of Changes in Bone Mineral Density in Postmenopausal Women Treated with Once-Weekly Bisphosphonates

In clinical practice, bone mineral density (BMD) determined by dual-energy x-ray absorptiometry is used to monitor response to osteoporosis therapy. However, 1 to 2 yr are usually required to assess patients' BMD responses. The possibility of earlier indicators of a response or nonresponse to treatment, such as changes in bone turnover markers (BTMs), is of interest to physicians and patients. In this post hoc analysis of women treated with once-weekly bisphosphonates, we examined the association of tertile percentage change from baseline in BTMs at 3 or 6 months and association of several baseline clinical characteristics with 24-month percentage change from baseline in BMD and with percentage of patients showing BMD nonresponse (defined as BMD loss at two or more of four sites) at 24 months. Multivariable analysis was performed to determine which factors were independently associated with BMD nonresponse. Patients in the tertile with the greatest decrease in each of the BTMs had the greatest mean increase in BMD and the lowest percentage of BMD nonresponders at 24 months. Several characteristics were independently associated with BMD nonresponse, including smaller 3-month reductions from baseline in serum C-terminal telopeptide of type 1 collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type 1 procollagen; younger age of menopause; a family history of osteoporosis; and higher baseline trochanteric BMD. Baseline BTMs were not predictive of 24-month BMD response to therapy. The strongest associations were for changes in BTMs with treatment. In groups of patients, short-term changes in markers of bone turnover appear to be predictors of longer term BMD response and nonresponse to bisphosphonate therapy.

Bone turnover markers are correlated with quantitative ultrasound of the calcaneus: 5-year longitudinal data

Associations between bone turnover markers and calcaneal ultrasound (quantitative ultrasound, QUS) were studied in a population-based sample of 810 elderly women. Baseline bone turnover markers correlated with baseline QUS as well as with 5-year prospective changes in QUS. Bone turnover markers are associated with areal bone mineral density, but the knowledge on the association with QUS is limited. Eight hundred ten women, all 75 years old, were investigated at baseline. Five hundred six completed a 5-year follow-up. Bone turnover markers and calcaneal QUS [speed of sound (SoS), broadband ultrasound attenuation (BUA), stiffness] were investigated at baseline. QUS was investigated at follow-up. All bone turnover markers were correlated with baseline QUS [standardized regression (Beta(std)) values from -0.07, p < 0.05 to -0.23, p < 0.001], with the exception of bone-specific alkaline phosphatase (S-Bone ALP) which was not correlated with BUA and stiffness index. When the correlations between baseline bone turnover markers and 5-year changes in QUS were analyzed, three serum osteocalcins were correlated with changes of SoS and stiffness index (Beta(std) = -0.11, p < 0.05 to -0.17, p < 0.001). Also S-CTX-I correlated with changes of SoS and stiffness index (Beta(std) = -0.10 and -0.09, respectively, p < 0.05). S-TRACP5b, urinary deoxypyridinoline/crea, and U-MidOC/crea correlated with changes of SoS (Beta(std) = -0.10 and p < 0.05 for all). S-Bone ALP did not correlate with change of QUS. None of the bone turnover markers correlated with changes of BUA. Bone turnover markers correlate with concomitantly assessed QUS as well as with longitudinal change in QUS.

High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over: the prospective MINOS study

Objectives:The association of bone turnover markers (BTM) with bone loss and fracture risk in men is poorly studied. The morphological basis of such a relationship is unknown. The objective of...

Allogeneic bone marrow transplantation is associated with a preferential femoral neck bone loss.

Osteoporosis is a major complication of organ transplantation. Little is known about the risk of developing osteoporosis in bone marrow transplant (BMT) recipients. We studied early and late changes in bone mineral density (BMD), as well as biochemical markers of bone remodeling, in patients at the time of allogeneic BMT (alloBMT) and up to 13 years thereafter. In a cross-sectional study, 102 patients (40 women, 62 men, mean age +/- SEM, 38.9 +/- 1.6 years) were segregated into a first group (A, n = 48) and evaluated before or during the first weeks (mean +/- SD 0.3 +/- 0.1 month, range -0.5 to 3 months) following alloBMT, and a second group (B, n = 54) studied 60.1 +/- 5.6 months (range 6-156 months) following alloBMT. Lumbar spine (LS) BMD was similar in groups A and B and was within normal limits. In contrast, femoral neck (FN) Z- and T-scores were significantly decreased in group B compared with group A (-0.68 +/- 0.14 vs -0.03 +/- 0.14 SD and -0.84 +/- 0.14 vs -0.22 +/- 0.14 SD, respectively; p < or = 0.002). Osteopenia (T-score between -1 and -2.5 SD) was present in 35% of group A and 43% of group B patients (NS). Osteoporosis (T-score < -2.5 SD) was detected in 7% of group B patients, but in none of those in group A (p = 0.05). In a longitudinal study, 56 subjects were evaluated at the time of alloBMT, and 33 and 23 were studied 6 or 12 months later, respectively (13 women, 20 men, 37.5 +/- 1.6 years). All were treated with supplements of calcium and vitamin D. Amenorrheic women received hormone replacement therapy (HRT). Three-monthly pamidronate infusions were given to 15 men and 10 non-amenorrheic women who were osteopenic/osteoporotic or had elevated baseline bone turnover markers. Mean baseline LS and FN Z- and T-scores were within normal range. Six months after BMT, FN BMD decreased by 4.2 +/- 0.7% (p < 0.001), and whole body BMD and bone mineral content by 1.5 +/- 0.4% and 3.1 +/- 0.6%, respectively (p < or = 0.0001). Twelve months after the graft, there was no further significant bone loss and only FN BMD decrease remained significantly different compared with baseline (-5.6 +/- 1.1%, p < or = 0.0001). These results indicate that the risk of decreased BMD is higher for the femoral neck than the lumbar spine and whole body levels in patients with allogeneic bone marrow transplantation, and that bone loss occurs mainly during the first 6 months after the graft.