Effects of cabozantinib on bone turnover markers in patients with metastatic renal cell carcinoma.

638 Background: In-vitro studies have shown that cabozantinib has a strong inhibitory action on osteoclast differentiation and bone-resorption activity. The aim of this analysis was to investigate the effects of cabozantinib on bone turnover markers in patients (pts) with metastatic renal cell carcinoma (mRCC). Methods: We included mRCC pts treated with cabozantinib within the Italian Managed Access Program (MAP) at the Istituto Nazionale Tumori of Milan (Italy). Plasma samples from every patient were collected at baseline and after 3 and 6 months of treatment. The bone resorption markers C-terminal telopeptide of type I collagen (CTx) and tartrate-resistant acid phosphatase isoenzyme 5b (TRACP 5b), the osteoclastogenesis markers osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), vitamin D and parathormone (PTH) were measured by immunometric assay techniques. Data were analyzed using the RM One-Way ANOVA test with Greenhouse-Geisser correction followed by uncorrected Fisher’s LSD multiple comparison tests with individual variances computed for each comparison. Statistical tests were performed using the program GraphPad Prism (San Diego, CA). Results: Twenty-two pts have been treated with cabozantinib. Mature data were available for 11 pts. Analysis of TRACP 5b, OPG, RANKL and vitamin D did not show any significant variations during treatment with cabozantinib. CTx showed a significant reduction after 6 months of treatment (MV 171.5 pg/mL, STD 208.4) from baseline (mean value [MV] 352.2 pg/mL, standard deviation [STD] 210.1) (p = 0.0439) in the whole study population. PTH levels significantly increased after 3 months of treatment (MV 86.79 pg/mL, STD 34.99) from baseline (MV 30.77 pg/mL, STD 12.64) (p = 0.0003), while significantly decreased after 6 months (MV 75.01 pg/mL, STD 53.1) (p = 0.0174). Conclusions: Our data suggested that cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx; it was also associated with an asymptomatic transient secondary increase of parathormone. This is the first clinical evidence on effects of cabozantinib on bone metabolism in a small population of mRCC pts.

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Effects of cabozantinib on bone turnover markers in real-world metastatic renal cell carcinoma

Tumori Journal ◽

10.1177/0300891620969817 ◽

2020 ◽

pp. 030089162096981

Author(s):

Raffaele Ratta ◽

Elena Verzoni ◽

Alessia Mennitto ◽

Francesco Pantano ◽

Antonia Martinetti ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Bone Resorption ◽

Bone Turnover ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Bone Turnover Markers ◽

The Mean ◽

Turnover Markers ◽

Paired Analysis

Background: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma. Methods: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves. Results: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population ( p = 0.013 and p < 0.0001, respectively), as well as at paired analysis ( p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months ( p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population ( p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively ( p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome. Conclusions: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.

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Diagnostic and Prognostic Validity of Serum Bone Turnover Markers in Metastatic Renal Cell Carcinoma

The Journal of Urology ◽

10.1016/j.juro.2006.06.028 ◽

2006 ◽

Vol 176 (4) ◽

pp. 1326-1331 ◽

Cited By ~ 22

Author(s):

Klaus Jung ◽

Michael Lein ◽

Martin Ringsdorf ◽

Jan Roigas ◽

Dietmar Schnorr ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Bone Turnover ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Bone Turnover Markers ◽

Turnover Markers

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RAD001 and zoledronic acid in renal cell carcinoma patients with bone metastases (RAZOR): A randomized phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15054 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15054-e15054

Author(s):

Reuben James Broom ◽

Vicky Hinder ◽

Katrina Sharples ◽

Janie Proctor ◽

Steven Duffey ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Zoledronic Acid ◽

Bone Turnover ◽

Bone Metastases ◽

Cell Carcinoma ◽

Renal Cell ◽

Bone Turnover Markers ◽

Treatment Naïve ◽

Prognostic Feature ◽

Turnover Markers

e15054 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause major morbidity and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (ZOL) reduces skeletal-related-events (SRE’s) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving ZOL. We sought to evaluate the effect on BM of RAD001 (everolimus) alone compared to RAD001 plus ZOL in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to RAD001 10mg daily (Arm A) vs. RAD001 + ZOL 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl], Arm B). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates or radiotherapy within 4 weeks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, weeks 1,4,8 and12. Treatment was continued on the allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12-weeks. The primary endpoint was urine N-telopeptide (uNTX) levels with plasma C-telopeptide (CTX) being secondary. Secondary objectives include comparison of quality of life (QoL) and pain (FACT-BP, BPI scores), SREs, safety and efficacy (PFS, RR). Results: Heng prognostic group was poor, intermediate and favorable-risk in; 40.0%, 46.7%, 13.3% respectively in Arm A and 20.0%, 46.7%, 33.3% (Arm B). 53.3% (Arm A) and 60.0% (Arm B) of pts had prior nephrectomy. Over the first 12 weeks, the reduction in mean CTX on Arm B relative to Arm A was 77% (95% CI (68%, 83%); p<0.0001). Median PFS was 7.5mo (95% CI 3.5, 14.7) in Arm B and 5.5mo (95% CI 3.2, 7.2) in Arm A (p=0.11). Data on uNTX, QoL and SREs will be presented. At data cut off, 8 pts in Arm B had stopped ZOL before progression with either a drop in CrCl or hypocalcaemia. No cases of osteonecrosis of the jaw were seen. Conclusions: The addition of ZOL to RAD001 significantly reduced the bone resorption marker CTX in this treatment-naïve RCC population of pts with the adverse prognostic feature of BM.

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RAD001 and zoledronic acid in patients with renal cell carcinoma with bone metastases (RAZOR): A randomized phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.402 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 402-402

Author(s):

Reuben James Broom ◽

Vicky Hinder ◽

Katrina Sharples ◽

Janie Proctor ◽

Steven Duffey ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Zoledronic Acid ◽

Bone Turnover ◽

Bone Metastases ◽

Cell Carcinoma ◽

Renal Cell ◽

Bone Turnover Markers ◽

Weekly Dose ◽

Prognostic Feature ◽

Turnover Markers

402 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause morbidity, and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (Z) reduces skeletal-related-events (SREs) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving Z. We sought to evaluate the effect on BM of RAD001 (R) (everolimus) alone compared to R+Z in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to R 10mg daily vs. R+Z 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl]). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates, or radiotherapy within 4 wks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, wks-1, 4, 8, and 12. Treatment was continued on allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12 wks. The primary endpoint was urine N-telopeptide (uNTX) level with secondary endpoints being plasma C-telopeptide (CTX), quality of life (FACT-BP, BPI), progression free survival (PFS), SREs, and safety. Results: Heng prognostic group poor, intermediate, and good risk was 20.0%, 46.7%, 33.3% in R+Z and 40.0%, 46.7%, 13.3% in R. Over first 12 wks, the reduction in mean: uNTX on R+Z relative to R was 68.4% (95% CI (60.1%, 74.9%); p<0.0001); CTX on R+Z relative to R was 77% (95% CI (68%, 83%); p<0.0001). For FACT-BP there was no evidence of a difference (p = 0.5) but addition of Z was favourable for BPI Severity -1.1 (-2.2, 0.23; p = 0.05) and BPI Interference -1.3 (-2.5, 0.03; p = 0.06). Median PFS was 7.5 mo (95% CI 3.4, 14.7) on R+Z and 4.6 mo (95% CI 3.2, 6.3) on R (p = 0.03). Median time to 1st SRE was 9.6 mo (95% CI 4.3, 15.5) on R+Z and 5.2 mo (95% CI 1.6-8.2) on R (p = 0.03). Conclusions: Addition of Z to R significantly reduced bone resorption markers in this RCC population of pts with the adverse prognostic feature of BM. Pts receiving R+Z had prolonged time to 1st SRE and PFS; larger studies are required to further evaluate the addition of bone-specific to targeted therapies in this disease. Clinical trial information: ACTRN12609000980235.

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The effects of sorafenib and sunitinib on bone turnover markers in patients with bone metastases from renal cell carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16145 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16145-e16145

Author(s):

C. Sahi ◽

J. J. Knox ◽

V. Hinder ◽

S. Deva ◽

D. Cole ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Bone Turnover ◽

Bone Metastases ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Serum Samples ◽

Baseline Serum ◽

Increased Risk ◽

Turnover Markers

e16145 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common and associated with poor outcomes. While the multi-tyrosine kinase inhibitors (TKI's) sunitinib and sorafenib have advanced the treatment of metastatic RCC, their efficacy on BM is unknown. Urinary N-telopeptide (uNTX) is a marker of bone turnover measured in nmol/mmol creatinine. Elevated uNTX levels correlate with an increased risk of skeletal related events and mortality in patients receiving bisphosphonates for BM from a range of primaries. In this pilot biomarker study we sought to prospectively evaluate the effects on BM of these multi-TKI's in RCC patients. Methods: Eligible patients had advanced RCC, at least one BM evident on imaging and no bisphosphonate exposure within 4 weeks. UNTX levels (OsteoMark) were measured at; baseline and weeks-1, 4, 8 and 12 after commencing either sunitinib or sorafenib. The primary endpoint was the percentage change (Ch) in uNTX levels from baseline. Serum samples were also collected for KIT and VEGFR-2 (Quantikine). Patients also completed pain (including bone pain) and quality of life questionnaires. Results: The uNTX results on the first 9 patients are presented in the table below (7 received sunitinib and 2 sorafenib). In this group, sVEGFR-2 and sKIT levels fell by week-1 and 4 respectively and at week-12 the mean % changes (95% CI) were -34% (-0.53,-0.14) and -38% (-0.58,-0.18). Conclusions: In patients with BM from RCC and at least moderately elevated uNTX levels at baseline, these multi-TKI's show a significant trend to decrease uNTX levels, but perhaps not as effectively as bone-specific therapies (e.g. bisphosphonates) do in other malignancies. SVEGFR-2 and sKIT levels also fell across the patient group over the same period. This pilot data raises questions about the activity of the multi-TKI's in BM from RCC and further research is needed. [Table: see text] [Table: see text]

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Bone turnover markers in relation to vitamin D status and disease activity in adults with systemic lupus erythematosus

Lupus ◽

10.1177/0961203318815593 ◽

2018 ◽

Vol 28 (2) ◽

pp. 156-162 ◽

Cited By ~ 5

Author(s):

A Sarkissian ◽

V Sivaraman ◽

S Bout-Tabaku ◽

S P Ardoin ◽

M Moore-Clingenpeel ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Vitamin D ◽

Bone Resorption ◽

Bone Turnover ◽

Disease Activity ◽

Lupus Erythematosus ◽

Bone Turnover Markers ◽

Systemic Lupus ◽

25 Hydroxy Vitamin D ◽

Turnover Markers

Objective Patients with systemic lupus erythematosus (SLE) have altered bone metabolism and are at risk of osteoporosis. The aim of this study was to examine bone turnover markers in relation to vitamin D, disease activity, and clinical risk factors in patients with established SLE. Methods Clinical registry and biorepository data of 42 SLE patients were assessed. Serum samples were analyzed for osteocalcin as a marker of bone formation, C-terminal telopeptide of type 1 collagen (CTX) as a marker for bone resorption, and 25-hydroxy vitamin D. Results Patients with a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI) score of 3 or greater had a lower median osteocalcin level ( P = 0.02) and lower 25-hydroxy vitamin D levels ( P = 0.03) than those with a score of less than 3. No significant differences in bone turnover markers were observed between patients dichotomized into subgroups using a 25-hydroxy vitamin D cut-off of 30 ng/mL or by a daily prednisone dose greater than or 5 mg or less. Osteocalcin levels were negatively correlated with SLEDAI scores ( P = 0.034), and were positively correlated with the CTX index (a ratio of measured CTX value to the upper limit of the normal value for age and gender) ( P < 0.01). No association between the CTX index and SLEDAI scores was found. Conclusion SLE disease activity may have direct effects on bone formation, but no effects on bone resorption in this cohort of established SLE patients, probably related to the inflammation-suppressing effects of glucocorticoids, thereby inhibiting cytokine-induced osteoclast activity. A fine balance exists between disease control and the use of glucocorticoids with regard to bone health.

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