Objective:To explore the expressions of serum N-terminal osteocalcin (N-MID) and cytokeratin (CK) 5/6 in primary lung cancer patients with bone metastasis and their clinical significances.Methods:The clinical data of 96 patients with primary lung cancer admitted to Chengdu Second People's Hospital between February 2019 to February 2022 were retrospectively analyzed. All patients were divided into the bone metastasis group (38 cases) and the non-bone metastasis group (58 cases) according to whether bone metastasis occurred, and 45 healthy people who underwent physical examination during the same period were treated as the healthy control group. The expression levels of serum N-MID and CK5/6 in the bone metastasis group, the non-bone metastasis group and the healthy control group were compared. Logistic regression was used to analyze the factors affecting bone metastasis in patients with primary lung cancer; receiver operating characteristic (ROC) curve analysis was used to analyze the value of the expression levels of serum N-MID and CK5/6 in predicting bone metastasis in patients with primary lung cancer.Results:The composition ratio of patients with pathological stage Ⅲ-Ⅳ, serum bone-derived alkaline phosphatase and N-MID expression levels in the bone metastasis group were higher than those in the non-bone metastasis group (all P < 0.05). The expression level of serum N-MID in the bone metastasis group and non-bone metastasis group was higher than that in the healthy control group [(26.0±5.3) ng/ml, (15.3±3.1) ng/ml vs. (9.9±1.7) ng/ml, F = 224.27, P < 0.001], and there were statistically significant differences in the serum N-MID expression level of the pairwise comparison among the three groups (all P < 0.05). The expression level of serum CK5/6 in the bone metastasis group and the non-bone metastasis group was lower than that in the healthy control group [(3.6±0.7) ng/ml, (7.3±1.4) ng/ml vs. (10.6±2.4) ng/ml, F = 178.11, P < 0.001], and there were statistically significant differences in the serum CK5/6 expression level of the pairwise comparison among the three groups (all P < 0.05). Multivariate analysis showed that CK5/6, N-MID and bone-derived alkaline phosphatase were independent affecting factors for bone metastasis in patients with primary lung cancer ( OR = 4.088, 3.615, 2.892, all P < 0.05). ROC curve analysis showed that the optimal cut-off values of serum N-MID and CK5/6 expression levels for predicting bone metastasis in patients with primary lung cancer were 18.59 ng/ml and 4.71 ng/ml; the corresponding the area under the curve (AUC) was 0.881 and 0.862, respectively; and the specificity and AUC of the combination of serum N-MID and CK5/6 in predicting the bone metastasis in patients with primary lung cancer was 98.28% and 0.937 (95% CI 0.869-0.977), respectively; the AUC predicted by the combination of both was higher than that by serum N-MID or CK5/6 single (all P < 0.001). Conclusions:The expression levels of serum N-MID and CK5/6 in primary lung cancer patients with bone metastasis are abnormally changed. Clinical detection of serum N-MID and CK5/6 expression levels may be used as sensitive indicators for predicting the bone metastasis in patients with primary lung cancer.