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.

introductionAs 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.

methodsA 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.

resultsSeventeen 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;

conclusionsOur 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.