Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press75010.17650/2313-805X-2026-13-1-46-61REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИReview ArticleMolecular mechanisms of bone metastasisМолекулярные механизмы костного метастазированияhttps://orcid.org/0000-0001-6975-51518557-4288ZaripovaAliya R.ЗариповаАлия Рамилевна
Russian Federation
al.zaripova@bk.ruhttps://orcid.org/0000-0002-0584-39696220-2619BermishevaM. A.БермишеваМарина Алексеевна
Russian Federation
marina_berm@mail.ruInstitute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of SciencesИнститут биохимии и генетики ФГБНУ «Уфимский федеральный исследовательский центр Российской академии наук»16032026131466110032025Copyright ©; 2026, Zaripova A.R., Bermisheva M.A.Copyright ©; 2026, Зарипова А.Р., Бермишева М.А.2026Zaripova A.R., Bermisheva M.A.Зарипова А.Р., Бермишева М.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/750

For various types of solid tumors, bones are the most common location of metastases. Bone is a dynamic organ capable of simultaneously performing multiple auxiliary functions in the body. Osteoblasts and osteoclasts and their changes play a significant role in bone remodeling.

Aim. To summarize current data on bone metastases for better understanding of biological nature of oncogenesis.

The article analyzes recent scientific publications containing information on molecular mechanisms of metastasis into the bone from the National Center for Biotechnology Information (NCBI), eLibrary and Google Scholar databases, as well as characterizes bone cells and their role in oncogenesis. Knowledge and deep understanding of bone metastasis in various solid tumors are necessary for development of accurate diagnostic methods and effective modern treatment of patients with bone metastases. Currently, the mechanisms of cancer metastasis and interactions between metastatic cancer cells and bone microenvironment are not completely understood. Epigenetic changes associated with differentiation of osteoblasts and osteoclasts and cell signal transduction play a large role in bone remodeling in various malignant neoplasms. Increased bone resorption is caused by disbalance between osteoblasts and osteoclasts. Osteoclast activity leads to release of growth factors from the bone matrix necessary for tumor cell multiplication in the bone.

В статье проанализированы научные публикации последних лет, содержащие сведения о молекулярных процессах метастазирования в костную ткань, из баз данных National Center for Biotechnology Information (NCBI), eLibrary и Google Scholar, а также охарактеризованы костные клетки и их роль в онкогенезе. Увеличение знаний и глубокое понимание процессов костного метастазирования при различных солидных опухолях необходимы для разработки точных методов диагностики и эффективного своевременного лечения пациентов с метастазами в костях. Выявлено, что в настоящее время механизмы метастазирования рака и взаимодействия метастатических раковых клеток с микроокружением кости полностью не изучены. Эпигенетические изменения, связанные с клеточной дифференцировкой остеобластов и остеокластов, а также с передачей клеточных сигналов, играют большую роль в ремоделировании кости при различных видах злокачественных новообразований. Повышенная резорбция кости вызвана дисбалансом между остеобластами и остеокластами. Активность остеокластов приводит к высвобождению из костного матрикса факторов роста, которые необходимы для размножения опухолевых клеток в кости.

bone metastasisbiomarkerpersonalized medicinebone microenvironmentкостный метастазбиомаркерперсонализированная медицинакостное микроокружениеZhang X., Miao J., Song Y. et al. Review on effects and mechanisms of plant-derived natural products against breast cancer bone metastasis. Heliyon 2024;10(18):e37894. DOI: 10.1016/j.heliyon.2024.e37894Yue Z., Niu X., Yuan Z. et al. RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. J Clin Invest 2022;132(2):e144579. DOI: 10.1172/JCI144579Springfeld C., Ferrone C.R., Katz M.H.G. et al. Neoadjuvant therapy for pancreatic cancer. Nat Rev Clin Oncol 2023;20(5):318–37. DOI: 10.1038/s41571-023-00746-1Zöllner S.K., Amatruda J.F., Bauer S. et al. Ewing sarcoma – diagnosis, treatment, clinical challenges and future perspectives. J Clin Med 2021;10(8):1685. DOI: 10.3390/jcm10081685Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;133(3421):571–3. DOI: 10.1016/S0140-6736(00)49915-0Taipaleenmäki H. Secreted microRNAs in bone metastasis. J Bone Miner Metab 2023;41(3):358–64. DOI: 10.1007/s00774-023-01424-zColeman R.E., Croucher P.I., Padhani A.R. et al. Bone metastases. Nat Rev Dis Primer 2020;6(1):83. DOI: 10.1038/s41572-020-00216-3Puppo M., Jaafar M., Diaz J.-J. et al. MiRNAs and snoRNAs in bone metastasis: functional roles and clinical potential. Cancers 2022;15(1):242–242. DOI: 10.3390/cancers15010242Sharma G., Sultana A., Abdullah K.M. et al. Epigenetic regulation of bone remodeling and bone metastasis. Semin Cell Dev Biol 2024;154:275–85. DOI: 10.1016/j.semcdb.2022.11.002Shibata H., Kato S., Sekine I. et al. Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology. ESMO Open 2016;1(2):e000037. DOI: 10.1136/esmoopen-2016-000037Nishimura K. Management of bone metastasis in prostate cancer. J Bone Miner Metab 2023;41(3):317–26. DOI: 10.1007/s00774-023-01435-wTang J., Gu Z., Yang Z. et al. Bibliometric analysis of bone metastases from lung cancer research from 2004 to 2023. Front Oncol 2024;14:1439209. DOI: 10.3389/fonc.2024.1439209Long N., Woodlock D., D’Agostino R. et al. Incidence and prevalence of bone metastases in different solid tumors determined by natural language processing of CT reports. Cancers 2025,17(2):218. DOI: 10.3390/cancers17020218Huang J.F., Shen J., Li X. et al. Incidence of patients with bone metastases at diagnosis of solid tumors in adults: a large population-based study. Ann Transl Med 2020;8(7):482. DOI: 10.21037/atm.2020.03.55Knapp B.J., Cittolin-Santos G.F., Flanagan M.E. et al. Incidence and risk factors for bone metastases at presentation in solid tumors. Front Oncol 2024;14:1392667. DOI: 10.3389/fonc.2024.1392667Nie H., Yuan Y., Li J. et al. Occurrence and distribution of bone metastases in 984 metastatic breast cancer patients. Transl Breast Cancer Res 2021;2. DOI: 10.21037/tbcr-20-64Hernandez R.K., Wade S.W., Reich A. et al. Incidence of bone metastases in patients with solid tumors: analysis of oncology electronic medical records in the United States. BMC Cancer 2018;18(1):44. DOI: 10.1186/s12885-017-3922-0Curtis E.M., Fuggle N.R., Cooper C. et al. Epigenetic regulation of bone mass. Best Pract Res Clin Endocrinol Metab 2022;36(2):101612. DOI: 10.1016/j.beem.2021.101612Weivoda M.M., Bradley E.W. Macrophages and bone remodeling. J Bone Miner Res 2023;38(3):359–69. DOI: 10.1002/jbmr.4773Nurullina G.M., Akhmadullina G.I. Bone remodeling in norm and in primary osteoporosis: the significance of bone remodeling markers. Arkhiv vnutrenney meditsiny = The Russian Archives of Internal Medicine 2018;8(2):100–10. (In Russ.). DOI: 10.20514/2226-6704-2018-8-2-100-110Нуруллина Г.М., Ахмадуллина Г.И. Костное ремоделирование в норме и при первичном остеопорозе: значение маркеров костного ремоделирования. Архивъ внутренней медицины 2018;8(2):100–10. DOI: 10.20514/2226-6704-2018-8-2-100-110Veis D.J., O’Brien C.A. Osteoclasts, master sculptors of bone. Annu Rev Pathol Mech Dis 2023;18(1):257–81. DOI: 10.1146/annurev-pathmechdis-031521-040919Zhang Y., Liang J., Liu P. et al. The RANK/RANKL/OPG system and tumor bone metastasis: potential mechanisms and therapeutic strategies. Front Endocrinol 2022;13:1063815. DOI: 10.3389/fendo.2022.1063815Silver S.A., Adhikari N.K., Bell C.M. et al. Nephrologist follow-up versus usual care after an acute kidney injury hospitalization (FUSION): a randomized controlled trial. Clin J Am Soc Nephrol 2021;16(7):1005–14. DOI: 10.2215/CJN.17331120Maylyan E.A. Multifactority of etiopathogenesis of osteoporosis and the role of genes of the canonical WNT-signaling pathway. Osteoporoz i osteopatii = Osteoporosis and Osteopathy 2015;18(2):15–9. (In Russ.). DOI: 10.14341/osteo2015215-19Майлян Э.А. Мультифакторность этиопатогенеза остеопороза и роль генов канонического WNT- сигнального пути. Остеопороз и остеопатии 2015;18(2):15–9. DOI: 10.14341/osteo2015215-19Ben-Ghedalia-Peled N., Vago R. Wnt Signaling in the development of bone metastasis. Cells 2022;11(23):3934. DOI: 10.3390/cells11233934Gerstein E.S., Timofeev Yu.S., Zuev A.A. et al. RANK/RANKL/OPG ligand-receptor system and its role in primary bone neoplasms (literature analysis and own data). Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2015;2(3):51–9. (In Russ.).Герштейн Е.С., Тимофеев Ю.С., Зуев А.А. и др. Лиганд-рецепторная система RANK/RANKL/OPG и ее роль при первичных новообразованиях костей (анализ литературы и собственные результаты). Успехи молекулярной онкологии 2015;2(3):51–9.Vičić I., Belev B. The pathogenesis of bone metastasis in solid tumors: a review. Croat Med J 2021;62(3):270–82. DOI: 10.3325/cmj.2021.62.270Pu D., Zhang H.E., Li L. Immune-related osteoblastic bone alterations mimicking bone metastasis in a small-cell lung cancer patient treated with durvalumab: a case report. Transl Lung Cancer Res 2024;13(8):2043–9. DOI: 10.21037/tlcr-24-461Lu K., Wang W., Liu Y. et al. Advancements in microenvironment-based therapies: transforming the landscape of multiple myeloma treatment. Front Oncol 2024;14:1413494. DOI: 10.3389/fonc.2024.1413494Elaasser B., Arakil N., Mohammad K.S. Bridging the gap in understanding bone metastasis: a multifaceted perspective. Int J Mol Sci 2024;25(5):2846. DOI: 10.3390/ijms25052846Luzzi K.J., MacDonald I.C., Schmidt E.E. et al. Multistep nature of metastatic inefficiency. Am J Pathol 1998;153(3):865–73. DOI: 10.1016/S0002-9440(10)65628-3Choi S.W., Sun A.K., Cheung J.P.-Y. et al. Circulating tumour cells in the prediction of bone metastasis. Cancers 2024;16(2):252. DOI: 10.3390/cancers16020252Choi S., Whitman M.A., Shimpi A.A. et al. Bone-matrix mineralization dampens integrin-mediated mechanosignalling and metastatic progression in breast cancer. Nat Biomed Eng 2023;7(11):1455–72. DOI: 10.1038/s41551-023-01077-3Ernst C., Wang H. Bone mineral slows down breast cancer cells. Nat Biomed Eng 2023;7(11):1346–7. DOI: 10.1038/s41551-023-01122-1Yalaev B.I., Tyurin A.V., Mirgalieva R.Y. et al. The role of DNA methylation in bone metabolism disorders. Vavilovskiy zhurnal genetiki i selektsii = Vavilov Journal of Genetics and Breeding 2019;23(1):67–74 (In Russ.). DOI: 10.18699/VJ19.463Ялаев Б.И., Тюрин А.В., Миргалиева Р.Я. и др. Роль метилирования ДНК в нарушении костного метаболизма. Вавиловский журнал генетики и селекции 2019;23(1):67–74. DOI: 10.18699/VJ19.463Sibuh B., Quazi S., Panday H. et al. The Emerging role of epigenetics in metabolism and endocrinology. Biology 2023;12(2):256. DOI: 10.3390/biology12020256Yang M., Wang A., Li C. et al. Methylation-induced silencing of ALDH2 facilitates lung adenocarcinoma bone metastasis by activating the MAPK pathway. Front Oncol 2020;10:1141. DOI: 10.3389/fonc.2020.01141Nishikawa K., Iwamoto Y., Kobayashi Y. et al. DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine–producing metabolic pathway. Nat Med 2015;21(3):281–7. DOI: 10.1038/nm.3774Scheid A.D., Beadnell T.C., Welch D.R. Roles of mitochondria in the hallmarks of metastasis. Br J Cancer 2021;124(1):124–35. DOI: 10.1038/s41416-020-01125-8Liu Z., Tian J., Peng F. et al. Hypermethylation of mitochondrial DNA facilitates bone metastasis of renal cell carcinoma. J Cancer 2022;13(1):304–12. DOI: 10.7150/jca.62278De Azevedo A.L.K., Gomig T.H.B., de Souza Fonseca Ribeiro E.М. Stress-induced phosphoprotein 1: how does this co-chaperone influence the metastasis steps? Clin Exp Metastasis 2024;41(5):589–97. DOI: 10.1007/s10585-024-10282-6Wang J., Zhao X., Qi J. et al. Eight proteins play critical roles in RCC with bone metastasis via mitochondrial dysfunction. Clin Exp Metastasis 2015;32(6):605–22. DOI: 10.1007/s10585-015-9731-4Ishikawa S., Umemura M., Nakakaji R. et al. EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma. Commun Biol 2024;7(1):567. DOI: 10.1038/s42003-024-06231-4Liu Z., Mao H., Chu D. et al. Clinical Implications of a six-protein signature in bone metastasis of renal cell carcinoma. J Cancer 2024;15(10):3034–44. DOI: 10.7150/jca.88612Ma W., Yan Y., Bai S. et al. SPARC expression in tumor microenvironment induces partial epithelial to mesenchymal transition of esophageal adenocarcinoma cells via cooperating with TGFβ signaling. Cell Biol Int 2023;47(1):250–9. DOI: 10.1002/cbin.11927Nätkin R., Pennanen P., Syvälä H. et al. Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation. PLoS One 2023;18(2):e0281645. DOI: 10.1371/journal.pone.0281645Matteucci E., Maroni P., Disanza A. et al. Coordinate regulation of microenvironmental stimuli and role of methylation in bone metastasis from breast carcinoma. Biochim Biophys Acta 2016;1863(1):64–76. DOI: 10.1016/j.bbamcr.2015.10.010Tu C., Wei L., Wang L. et al. Eight differential miRNAs in DN identified by microarray analysis as novel biomarkers. Diabetes Metab Syndr Obes Targets Ther 2022;15:907–20. DOI: 10.2147/DMSO.S355783Zaib S., Rana N., Khan I. Histone modifications and their role in epigenetics of cancer. Curr Med Chem 2022;29(14):2399–411. DOI: 10.2174/0929867328666211108105214Edwards C.M., Johnson R.W. Targeting Histone Modifications in Bone and Lung Metastatic. Cancers 2021;19(3):230–46. DOI: 10.1007/s11914-021-00670-2Wang C., Zhang H., Wang X. et al. Targeting BRD4 to attenuate RANKL-induced osteoclast activation and bone erosion in rheumatoid arthritis. Mol Cell Biochem 2024;480(3):1669–84. DOI: 10.1007/s11010-024-05073-2Li Z., Liu P., Chen W. et al. Hypoxia-cleavable and specific targeted nanomedicine delivers epigenetic drugs for enhanced treatment of breast cancer and bone metastasis. J Nanobiotechnology 2023;21(1):221. DOI: 10.1186/s12951-023-01939-7Searcy M.B., Johnson R.W. Epigenetic control of the vicious cycle. J Bone Oncol 2024;44:100524. DOI: 10.1016/j.jbo.2024.100524Raji L., Tetteh A., Amin A.R.M.R. Role of c-Src in carcinogenesis and drug resistance. Cancers 2023;16(1):32. DOI: 10.3390/cancers16010032Lu Y., Chan Y.-T., Tan H.-Y. et al. Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy. Mol Cancer 2020;19(1):79. DOI: 10.1186/s12943-020-01197-3Zhang W., Bado I.L., Hu J. et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 2021;184(9):2471–86.e20. DOI: 10.1016/j.cell.2021.03.011Maroni P., Gomarasca M., Lombardi G. Long non-coding RNAs in bone metastasis: progresses and perspectives as potential diagnostic and prognostic biomarkers. Front Endocrinol 2023;14:1156494. DOI: 10.3389/fendo.2023.1156494Wang X., Gong Z., Ma L. et al. LncRNA GACAT1 induces tongue squamous cell carcinoma migration and proliferation via miR149. J Cell Mol Med 2021;25(17):8215–21. DOI: 10.1111/jcmm.16690Wen S., Wei Y., Zen C. et al. Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine. Mol Cancer 2020;19(1):171. DOI: 10.1186/s12943-020-01293-4Lang C., Yin C., Lin K. et al. m6 A modification of lncRNA PCAT6 promotes bone metastasis in prostate cancer through IGF2BP2 mediated IGF1R mRNA stabilization. Clin Transl Med 2021;11(6):e426. DOI: 10.1002/ctm2.426Li K.X., Sun X., Li B.Y. et al. Conversion of osteoclasts into bone-protective, tumor-suppressing cells. Cancers 2021;13(22):5593. DOI: 10.3390/cancers13225593Bonci D., Coppola V., Patrizii M. et al. A microRNA code for prostate cancer metastasis. Oncogene 2016;35(9):1180–92. DOI: 10.1038/onc.2015.176Takai M., Mori S., Honoki K. et al. Roles of lysophosphatidic acid (LPA) receptor-mediated signaling in cancer cell biology. J Bioenerg Biomembr 2024;56(4):475–82. DOI: 10.1007/s10863-024-10028-9Liu Y., Chen H., Chen T. et al. The emerging role of osteoclasts in the treatment of bone metastases: rationale and recent clinical evidence. Front Oncol 2024;14:1445025. DOI: 10.3389/fonc.2024.1445025Puppo M., Valluru M.K., Clézardin P. MicroRNAs and their roles in breast cancer bone metastasis. Curr Osteoporos Rep 2021;19(3):256–63. DOI: 10.1007/s11914-021-00677-9Taipaleenmäki H., Farina N.H., van Wijnen A.J. et al. Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget 2016;7(48):79032–46. DOI: 10.18632/oncotarget.12593Shojaei S., Moradi-Chaleshtori M., Paryan M. et al. Mesenchymal stem cell-derived exosomes enriched with miR-218 reduce the epithelial–mesenchymal transition and angiogenesis in triple-negative breast cancer cells. Eur J Med Res 2023;28(1):516. DOI: 10.1186/s40001-023-01463-2Ariffin S.H.Z., Wahab R.M.A., Razak M.A. et al. Evaluation of in vitro osteoblast and osteoclast differentiation from stem cell: a systematic review of morphological assays and staining techniques. PeerJ 2024;12:e17790. DOI: 10.7717/peerj.17790Kostenuik P.J., Nguyen H.Q., McCabe J. et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 2009;24(2):182–95. DOI: 10.1359/jbmr.081112Polyzos S.A., Makras P., Tournis S., Anastasilakis A.D. Off-label uses of denosumab in metabolic bone diseases. Bone 2019;129:115048. DOI: 10.1016/j.bone.2019.115048Keizer R.J., Huitema A.D., Damen C.W. et al. The pharmacokinetics of monoclonal antibodies. Ned Tijdschr Geneeskd 2007;151(12):683–8. (In Dutch).Lu J., Hu D., Zhang Y. et al. Current comprehensive understanding of denosumab (the RANKL neutralizing antibody) in the treatment of bone metastasis of malignant tumors, including pharmacological mechanism and clinical trials. Front Oncol 2023;13:1133828. DOI: 10.3389/fonc.2023.1133828Cheung Y.M.M., Morgans A., Hamnvik O.P.R. Bone health and denosumab discontinuation in oncology populations. Oncologist 2022;27(12):998–1003. DOI: 10.1093/oncolo/oyac213Rodan G.A., Fleisch H.A. Bisphosphonates: mechanisms of action. J Clin Invest 1996;97(12):2692–6. DOI: 10.1172/JCI118722Lu K.H., Lu E.W,, Lin C.W. et al. New insights into molecular and cellular mechanisms of zoledronate in human osteosarcoma. Pharmacol Ther 2020;214:107611. DOI: 0.1016/j.pharmthera.2020.107611Liu R., Li Z., Chen R. et al. EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction. Nat Commun 2025;16(1):1206. DOI: 10.1038/s41467-025-56506-5Tang M., Gong M., Liu X. et al. Recent update on the development of EZH2 inhibitors and degraders for cancer therapy. Eur J Med Chem 2025;299:118106. DOI: 10.1016/j.ejmech.2025.118106Verza F. A., Das U., Fachin A.L. et al. Roles of histone deacetylases and inhibitors in anticancer therapy. Cancers (Basel) 2020;12(6):1664. DOI: 10.3390/cancers12061664Clements M.E., Holtslander L., Johnson J.R., Johnson R.W. Select HDAC inhibitors enhance osteolysis and bone metastasis outgrowth but can be mitigated with bisphosphonate therapy. JBMR Plus 2023;7(3):e10694. DOI: 10.1002/jbm4.10694Dang L., Liu J., Li F. et al. Targeted delivery systems for molecular therapy in skeletal disorders. Int J Mol Sci 2016;17(3):428. DOI: 10.3390/ijms17030428Sekido T., Sakura N., Higashi Y. et al. Novel drug delivery system to bone using acidic oligopeptide: pharmacokinetic characteristics and pharmacological potential. J Drug Target 2001;9(2):111–121. DOI: 10.3109/10611860108997922Yan Y., Gao X., Zhang S. et al. Carboxyl-terminated dendrimer enables osteolytic lesion targeting and photothermal ablation of malignant bone tumors. ACS Appl Mater Interfaces 2019;11: 160–8. DOI: 10.1021/acsami.8b15827Gupta N., Devgan A., Bansal I. et al. Usefulness of radium-223 in patients with bone metastases. Proc (Bayl Univ Med Cent) 2017;30(4):424–6. DOI: 10.1080/08998280.2017.11930213Lunan M., Raval A.D., Phan N.T. N. et al. Effectiveness and safety of radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC): a systematic literature review of 48 real-world studies. J Clin Oncol 2025;43(5):81. DOI: 10.1200/JCO.2025.43.5_suppl.81Liu Z., Zhang X., Ben T. et al. Focal adhesion in the tumour metastasis: from molecular mechanisms to therapeutic targets. Biomark Res 2025;13(1):38. DOI: 10.1186/s40364-025-00745-7Hussain M., Le Moulec S., Gimmi C. et al. Differential effect on bone lesions of targeting integrins: randomized phase II trial of abituzumab in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res 2016;22(13):3192–200. DOI: 10.1158/1078-0432.CCR-15-2512