Comparative evaluation of four categories of serum biomarkers for detecting bone metastasis in lung cancer: a systematic review and meta-analysis of 119 studies

Abstract Background Bone metastasis in lung cancer worsens prognosis, highlighting the need for reliable serum biomarkers for early detection and risk stratification. Methods Five databases were searched. Study selection, data extraction, and quality assessment were performed. Meta-analyses were conducted to assess the association between biomarkers and bone metastasis. Heterogeneity was assessed using Cochran’s Q and I 2 tests. Subgroup analyses, meta-regression, and sensitivity analyses were performed, and publication bias was evaluated using funnel plots, Egger’s test, and the trim-and-fill analysis. Results A total of 119 studies involving 12,409 patients were included. Pooled analyses showed significant associations between bone metastasis and several biomarkers, including traditional tumor markers: CEA (SMD = 3.03, 95% CI 2.52–3.55, P < 0.001), CA125 (SMD = 3.82, 95% CI 3.04–4.60, P < 0.001), CA153 (SMD = 2.52, 95% CI 0.98–4.06, p = 0.001), and CYFRA21-1 (SMD = 1.68, 95% CI 1.37–1.99, P < 0.001); bone formation markers: bALP (SMD = 2.84, 95% CI 1.78–3.90, P < 0.001), T-ALP (SMD = 1.28, 95% CI 0.43–2.13, p = 0.003), PINP (SMD = 1.59, 95% CI 1.10–2.07, P < 0.001), and N-MID (SMD = 0.86, 95% CI 0.37–1.36, p = 0.001); bone resorption markers: β-CTX (SMD = 1.35, 95% CI 0.82–1.88, P < 0.001), NTx (SMD = 1.74, 95% CI 1.07–2.41, P < 0.001), and ICTP (SMD = 2.11, 95% CI 1.50–2.72, P < 0.001); and bone microenvironment and regulatory factors: BSP (SMD = 1.62, 95% CI 1.21–2.02, P < 0.001), ODF (SMD = 4.59, 95% CI 3.92–5.25, P < 0.001), calcium (SMD = 1.18, 95% CI 0.77–1.60, P < 0.001), OCIF (SMD = 4.97, 95% CI 3.64–6.30, P < 0.001), PTHrP (SMD = 0.88, 95% CI 0.68–1.08, P < 0.001), calcitonin (SMD = 1.81, 95% CI 0.48–3.15, p = 0.008), and calcineurin (SMD = 3.51, 95% CI 2.31–4.71, P < 0.001). In contrast, NSE, CICP, osteocalcin, CTX, TRACP-5b, and RANKL/OPG were not consistently associated. Subgroup and sensitivity analyses confirmed the robustness of most findings, though heterogeneity and publication bias were noted. Conclusions Multiple serum biomarkers are associated with lung cancer bone metastasis and may serve as complementary tools for early detection and risk stratification.