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What is the relationship between bone turnover markers and skeletal-related events in patients with bone metastases from solid tumors and in patients with multiple myeloma? A systematic review and meta-regression analysis.

ABSTRACT: Introduction:As a result of the negative impact of bone metastases on patient quality of life, it is important to identify patients at increased risk of skeletal-related events (SREs). Biochemical markers produced by osteoblasts and osteoclasts may provide an early indicator of treatment response to antiresorptive therapy. We aimed to explore the relationship between change in the urinary bone turnover marker cross-linked N-terminal telopeptide of type 1 collagen (uNTX) at the earliest time of steady state and risk of SREs. Methods:A comprehensive search of eight bibliographic databases and two trial registries was conducted (June 2017). We included randomized controlled trials of adults (?18 years old) with bone metastases from solid tumors (including breast, lung, prostate) or bone lesions from multiple myeloma that compared denosumab or bisphosphonate(s) with each other or a placebo. Meta-analyses were used to evaluate the relationship between uNTX and SREs. The primary outcomes were based on uNTX at week 13 and SREs in those studies. Results:Seventeen studies (12,130 patients) were included. The analysis results indicated a positive association between uNTX reduction, measured by the between-group difference of the natural logarithm of the ratio between uNTX at week 13 and baseline, and SRE risk reduction, measured by the natural logarithm of the hazard ratio (HR) for time to first SRE between the two groups (uNTX effect on SRE risk, defined as SRE HR increase corresponding to one unit smaller in the magnitude of uNTX reduction: 0.3560, 95% confidence interval 0.0249-0.6871; P = .0390, R2 = 0.7360). Results were similar for studies that reported change in uNTX from baseline to week 13 and to later than week 13. The limitation of this review is that it depends on how comprehensive study data were that could be included in the meta-regression. Conclusions:Our findings support a positive relationship between reduction of bone turnover markers at the earliest time of steady state and reduction in longer-term risk of SREs.

SUBMITTER: Jiang Z

PROVIDER: S-EPMC7215099 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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What is the relationship between bone turnover markers and skeletal-related events in patients with bone metastases from solid tumors and in patients with multiple myeloma? A systematic review and meta-regression analysis.

Jiang Zefei Z Tang En-Tzu ET Li Chuang C Zhu Li L Zhang Biao B Glennane Tony T Zhang Li L

Bone reports 20200423

<h4>Introduction</h4>As a result of the negative impact of bone metastases on patient quality of life, it is important to identify patients at increased risk of skeletal-related events (SREs). Biochemical markers produced by osteoblasts and osteoclasts may provide an early indicator of treatment response to antiresorptive therapy. We aimed to explore the relationship between change in the urinary bone turnover marker cross-linked N-terminal telopeptide of type 1 collagen (uNTX) at the earliest t ...[more]

PMID: 32420416

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Project description:BackgroundClinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation.PurposeWe aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment.MethodsUsing the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted.ResultsA total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19-89) years with a median duration of denosumab treatment of 253 (range, 88-2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer.ConclusionThis analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient's need to continue denosumab treatment and improve patient outcomes.

Project description:BackgroundLittle is known on how denosumab reduces skeletal-related events (SREs) by bone metastases from solid tumors. We sought to evaluate the effect of denosumab administration in patients with bone metastases from solid tumors.MethodsData of patients treated with denosumab were collected from electronic medical charts (n = 496). Eligible participants in this study were adult patients (age ≥ 18 years) with metastatic bone lesions from solid tumors treated with denosumab. SREs, surgical interventions, the spinal instability neoplastic score (SINS) for spinal region, and Mirels' score for the appendicular region were evaluated. To assess whether denosumab could prevent SREs and associated surgery, the SINS and Mirels' score were compared between patients with and without SREs.ResultsA total of 247 patients (median age, 65.5 years old; median follow-up period, 13 months) treated with denosumab for metastatic bone lesions from solid tumors were enrolled in this study. SREs occurred in 19 patients (7.7%). SREs occurred in 2 patients (0.8%) who took denosumab administration before SREs. Surgical interventions were undertaken in 14 patients (5.7%) (spinal and intradural lesions in five patients and appendicular lesions in nine patients). The mean SINS of patients without SREs compared to those with SREs were 7.5 points and 10.2 points, respectively. The mean Mirels' scores of non-SREs patients and those with SREs were 8.07 points and 10.7 points, respectively. Patients with SREs had significantly higher Mirels' score than non-SREs patients (p < 0.01). Patients with SREs had higher SINS than non-SREs patients (p = 0.09).ConclusionsSREs occurred in patients with higher SINS or Mirels' scores. Two patients suffered from SREs though they took denosumab administration before SREs. Appropriate management of denosumab for patients with bone metastasis is significant. Surgical interventions may be needed for patients who with higher SINS or Mirel's scores.

Dataset Information

What is the relationship between bone turnover markers and skeletal-related events in patients with bone metastases from solid tumors and in patients with multiple myeloma? A systematic review and meta-regression analysis.

Publications

What is the relationship between bone turnover markers and skeletal-related events in patients with bone metastases from solid tumors and in patients with multiple myeloma? A systematic review and meta-regression analysis.

Similar Datasets

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