Abstract：Objective To examine the causal association and potential mechanisms between bone mineral density in different age groups and primary malignant bone tumor based on two sample Mendelian randomization (MR), so as to provide a reference for the prevention and treatment of primary malignant bone tumor. Methods The genome-wide association study (GWAS) of bone mineral density was obtained from the GEFOS database,which included 66 628 subjects divided into five age groups (0-15, 15-30, 30-45, 45-60, and >60 years) based on the phases of human bone development. The GWAS of primary malignant bone tumor was sourced from the FinnGen database, including 648 cases and 378 749 controls. Using bone mineral density of five age groups as the exposure and primary malignant bone tumor as the outcome, an MR analysis was performed with the inverse-variance weighted (IVW) method. Sensitivity analysis were conducted using Cochran's Q test, MR-Egger regression, MR-PRESSO test and MR Steiger test. The potential mechanisms underlying the causal association between bone density and primary malignant bone tumors were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results The MR analysis results showed that there was a negative causal association between bone density and primary malignant bone tumors in the 30-45 age group (OR=0.301, 95%CI: 0.126-0.721). No statistically significant associations between bone density and primary malignant bone tumors were found in the 0-15, 15-30, 45-60, and >60 age groups (all P>0.05). Sensitivity analysis did not detect heterogeneity, pleiotropy (all P>0.05) and reverse causality. KEGG enrichment analysis revealed that genes highly associated with bone density and primary malignant bone tumors were enriched in the mTOR signaling pathway and the Wnt signaling pathway, among which Low Density lipoprotein Receptor Related protein 5 and Wnt Family Member 16 are key regulatory genes. Conclusion The decrease in bone mineral density among individuals aged 30-45 may increase the risk of primary malignant bone tumors through the mTOR signaling pathway and the Wnt signaling pathway.
王曼怡, 吴菁菁, 李晓珊, 张慧茹, 黄智凯, 曾谷清. 不同年龄分组的骨密度与原发性恶性骨肿瘤的孟德尔随机化研究[J]. 预防医学, 2025, 37(6): 612-615.
WANG Manyi, WU Jingjing, LI Xiaoshan, ZHANG Huiru, HUANG Zhikai, ZENG Guqing. Association between bone mineral density in different age groups and primary malignant bone tumor: a Mendelian randomization study. Preventive Medicine, 2025, 37(6): 612-615.
[1] ANDERSON W J,DOYLE L A.Updates from the 2020 World Health Organization classification of soft tissue and bone tumours[J].Histopathology,2021,78(5):644-657. [2] XU Y,SHI F Q,ZHANG Y T,et al.Twenty-year outcome of prevalence,incidence,mortality and survival rate in patients with malignant bone tumors[J].Int J Cancer,2024,154(2):226-240. [3] HORIUCHI K,NEMOTO R,MIZUNO T,et al.Prevalence of low bone mineral density and risk of fractures in osteosarcoma and Ewing's sarcoma survivors:a scoping review[J/OL].J Bone Oncol,2023,38[2025-04-17].https://doi.org/10.1016/j.jbo.2022.100464. [4] LEE H F,WU C E,LIN Y S,et al.Low bone mineral density may be associated with long-term risk of cancer in the middle-aged population:a retrospective observational study from a single center[J].J Formos Med Assoc,2018,117(4):339-345. [5] RAN S,ZHANG S Y,CHEN H T,et al.Total body bone mineral density and severe COVID-19:a Mendelian randomization analysis in five age strata[J/OL].Bone,2022,155[2025-04-17].https://doi.org/10.1016/j.bone.2021.116281. [6] BURGESS S,THOMPSON S G.Mendelian randomization:methods for causal inference using genetic variants[M].2nd ed.New York:CRC Press,2021. [7] MEDINA-GOMEZ C,KEMP J P,TRAJANOSKA K,et al.Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects[J].Am J Hum Genet,2018,102(1):88-102. [8] SKRIVANKOVA V W,RICHMOND R C,WOOLF B A R,et al.Strengthening the reporting of observational studies in epidemiology using Mendelian randomization:the STROBE-MR Statement[J].JAMA,2021,326(16):1614-1621. [9] CAO Z Q,WU Y D,LI Q X,et al.A causal relationship between childhood obesity and risk of osteoarthritis:results from a two-sample Mendelian randomization analysis[J].Ann Med,2022,54(1):1636-1645. [10] LUTZ S M,VOORHIES K,WU A C,et al.The influence of unmeasured confounding on the MR Steiger approach[J].Genet Epidemiol,2022,46(2):139-141. [11] WU H H,WU B,ZHANG S J,et al.Establishing age-adjusted trabecular bone score curves using dual-energy X-ray absorptiometry in Chinese women and men:a cross-sectional study[J].Quant Imaging Med Surg,2023,13(4):2478-2485. [12] 施涛,魏嘉.恶性肿瘤骨转移靶向治疗及免疫治疗进展[J].中国肿瘤临床,2021,48(21):1093-1099. SHI T,WEI J.Advances in targeted therapy and immunotherapy for bone metastases of malignant tumors[J].Chin J Clin Oncol,2021,48(21):1093-1099.(in Chinese) [13] GEMAYEL J,CHAKER D,EL HACHEM G,et al.Mesenchymal stem cells-derived secretome and extracellular vesicles:perspective and challenges in cancer therapy and clinical applications[J].Clin Transl Oncol,2023,25(7):2056-2068. [14] SADYKOVA L R,NTEKIM A I,MUYANGWA-SEMENOVA M,et al.Epidemiology and risk factors of osteosarcoma[J].Cancer Invest,2020,38(5):259-269. [15] VALENZUELA C A,QUINTANILLA R,OLATE-BRIONES A,et al.SASP-dependent interactions between senescent cells and platelets modulate migration and invasion of cancer cells[J].Int J Mol Sci,2019,20(21):1-17. [16] SIMCOX J,LAMMING D W.The central moTOR of metabolism[J].Dev Cell,2022,57(6):691-706. [17] 张宗瑞,尹恒,张强,等.骨质疏松进程中破骨细胞能量代谢重编程研究进展[J].中国骨质疏松杂志,2022,28(11):1664-1669. ZHANG Z R,YIN H,ZHANG Q,et al.Research progress in energy metabolism reprogramming of osteoclasts in the process of osteoporosis[J].Chin J Osteopor,2022,28(11):1664-1669.(in Chinese) [18] BEK J W,SHOCHAT C,DE CLERCQ A,et al.Lrp5 mutant and crispant zebrafish faithfully model human osteoporosis,establishing the zebrafish as a platform for CRISPR-based functional screening of osteoporosis candidate genes[J].J Bone Miner Res,2021,36(9):1749-1764.
