Cancer-related bone erosion occurs frequently in bone metastasis and is associated with severe complications such as chronic bone pain, fractures, and lower survival rates. In recognition of the fact that the darkness hormone melatonin is capable of regulating bone homeostasis, we explored its therapeutic potential in bone metastasis. We found that melatonin directly reduces osteoclast differentiation, bone resorption activity and promotes apoptosis of mature osteoclasts. We also observed that melatonin inhibits RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which in turn prevents cancer-associated osteoclast differentiation. In lung and prostate bone metastasis models, twice-weekly melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions. Melatonin also substantially lowered the numbers of TRAP-positive osteoclasts in tibia bone marrow and RANKL expression in tumor tissue. These findings show promise for melatonin in the treatment of bone metastases.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Chin H, Kim J. Bone Metastasis: Concise Overview. Fed Pract: Health Care Prof VA, DoD, PHS. 2015;32:24–30.
Singh VA, Haseeb A, Alkubaisi AA. Incidence and outcome of bone metastatic disease at University Malaya Medical Centre. Singap Med J. 2014;55:539–46.
Svensson E, Christiansen CF, Ulrichsen SP, Rorth MR, Sorensen HT. Survival after bone metastasis by primary cancer type: a Danish population-based cohort study. BMJ Open. 2017;7:e016022.
Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone metastases: an overview. Oncol Rev. 2017;11:321.
Schmid-Alliana A, Schmid-Antomarchi H, Al-Sahlanee R, Lagadec P, Scimeca JC, Verron E. Understanding the progression of bone metastases to identify novel therapeutic targets. Int J Mol Sci. 2018;19:148.
Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6:2609–17.
Lyu H, Jundi B, Xu C, Tedeschi SK, Yoshida K, Zhao S, et al. Comparison of Denosumab and Bisphosphonates in patients with osteoporosis: a meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2019;104:1753–65.
Steger GG, Bartsch R. Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion. Ther Adv Med Oncol. 2011;3:233–43.
Benjamin B, Benjamin MA, Swe M, Sugathan S. Review on the comparison of effectiveness between denosumab and bisphosphonates in post-menopausal osteoporosis. Osteoporos Sarcopenia. 2016;2:77–81.
Wutzl A, Eisenmenger G, Hoffmann M, Czerny C, Moser D, Pietschmann P, et al. Osteonecrosis of the jaws and bisphosphonate treatment in cancer patients. Wien Klinische Wochenschr. 2006;118:473–8.
Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiodt M. Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat Rev. 2018;69:177–87.
Amaral FGD, Cipolla-Neto J. A brief review about melatonin, a pineal hormone. Arch Endocrinol Metab. 2018;62:472–9.
Slominski AT, Hardeland R, Zmijewski MA, Slominski RM, Reiter RJ, Paus R. Melatonin: a cutaneous perspective on its production, metabolism, and functions. J Invest Dermatol. 2018;138:490–9.
Wang B, Wen H, Smith W, Hao D, He B, Kong L. Regulation effects of melatonin on bone marrow mesenchymal stem cell differentiation. J Cell Physiol. 2019;234:1008–15.
Golan K, Kumari A, Kollet O, Khatib-Massalha E, Subramaniam MD, Ferreira ZS, et al. Daily onset of light and darkness differentially controls hematopoietic stem cell differentiation and maintenance. Cell Stem Cell. 2018;23:572–85 e577.
Golan K, Kollet O, Markus RP, Lapidot T. Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: the role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles. Exp Hematol. 2019;78:1–10.
Cordoba-Moreno MO, de Souza EDS, Quiles CL, Dos Santos-Silva D, Kinker GS, Muxel SM, et al. Rhythmic expression of the melatonergic biosynthetic pathway and its differential modulation in vitro by LPS and IL10 in bone marrow and spleen. Sci Rep. 2020;10:4799.
Markus RP, Fernandes PA, Kinker GS, da Silveira Cruz-Machado S, Marcola M. Immune-pineal axis – acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes. Br J Pharm. 2018;175:3239–50.
Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, et al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15:434–43.
Arendt J. Melatonin and human rhythms. Chronobiol Int. 2006;23:21–37.
Anderson G, Rodriguez M. Multiple sclerosis: the role of melatonin and N-acetylserotonin. Mult Scler Relat Disord. 2015;4:112–23.
Jahanban-Esfahlan R, Mehrzadi S, Reiter RJ, Seidi K, Majidinia M, Baghi HB, et al. Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes. Br J Pharm. 2018;175:3230–8.
Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, et al. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8:39896–921.
Lv JW, Zheng ZQ, Wang ZX, Zhou GQ, Chen L, Mao YP, et al. Pan-cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types. J Pineal Res. 2019;66:e12557.
Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 melatonin receptors: a therapeutic perspective. Annu Rev Pharmacol Toxicol. 2016;56:361–83.
Leaw B, Nair S, Lim R, Thornton C, Mallard C, Hagberg H. Mitochondria, bioenergetics and excitotoxicity: new therapeutic targets in perinatal brain injury. Front Cell Neurosci. 2017;11:199.
Boafo A, Greenham S, Alenezi S, Robillard R, Pajer K, Tavakoli P, et al. Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective. Nat Sci Sleep. 2019;11:1–10.
Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Biophys. 2008;473:201–9.
Roth JA, Kim BG, Lin WL, Cho MI. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem. 1999;274:22041–7.
Kim HJ, Kim HJ, Bae MK, Kim YD. Suppression of osteoclastogenesis by melatonin: a melatonin receptor-independent action. Int J Mol Sci. 2017;18:1142.
Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res: Off J Am Soc Bone Miner Res. 2002;17:1219–29.
Lopez-Canul M, Min SH, Posa L, De Gregorio D, Bedini A, Spadoni G, et al. Melatonin MT1 and MT2 receptors exhibit distinct effects in the modulation of body temperature across the light/dark cycle. Int J Mol Sci. 2019;20:2452.
Watkins LR, Orlandi C, Orphan G. Protein coupled receptors in affective disorders. Genes. 2020;11:694.
Chao CC, Chen PC, Chiou PC, Hsu CJ, Liu PI, Yang YC, et al. Melatonin suppresses lung cancer metastasis by inhibition of epithelial-mesenchymal transition through targeting to Twist. Clin Sci. 2019;133:709–22.
Bi H, Chen X, Gao S, Yu X, Xiao J, Zhang B, et al. Key triggers of osteoclast-related diseases and available strategies for targeted therapies: a review. Front Med. 2017;4:234.
Shupp AB, Kolb AD, Mukhopadhyay D, Bussard KM. Cancer metastases to bone: concepts, mechanisms, and interactions with bone osteoblasts. Cancers. 2018;10:182.
Kim JH, Kim N. Signaling pathways in osteoclast differentiation. Chonnam Med J. 2016;52:12–7.
Guise TA, Chirgwin JM. Transforming growth factor-beta in osteolytic breast cancer bone metastases. Clin Orthop Relat Res. 2003;(415 Suppl):S32–8.
Fowler TW, Kamalakar A, Akel NS, Kurten RC, Suva LJ, Gaddy D. Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures. J Cell Sci. 2015;128:683–94.
van Dam PA, Verhoeven Y, Jacobs J, Wouters A, Tjalma W, Lardon F, et al. RANK-RANKL signaling in cancer of the uterine cervix: a review. Int J Mol Sci. 2019;20:2183.
Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, et al. Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-kappaB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun. 2000;275:768–75.
Watanabe M, Kobayashi Y, Takahashi N, Kiguchi K, Ishizuka B. Expression of melatonin receptor (MT1) and interaction between melatonin and estrogen in endometrial cancer cell line. J Obstet Gynaecol Res. 2008;34:567–73.
Cutando A, Lopez-Valverde A, Dev J, Gimenez JL, Carcia IA, Ded RG. Action of melatonin on squamous cell carcinoma and other tumors of the oral cavity (Review). Oncol Lett. 2014;7:923–6.
Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, et al. Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res. 2013;23:267–300.
Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:6243s–9s.
Maria S, Samsonraj RM, Munmun F, Glas J, Silvestros M, Kotlarczyk MP, et al. Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res. 2018;64: https://doi.org/10.1111/jpi.12465.
Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Prim. 2018;4:18002.
Bang J, Chang HW, Jung HR, Cho CH, Hur JA, Lee SI, et al. Melatonin attenuates clock gene cryptochrome1, which may aggravate mouse anti-type II collagen antibody-induced arthritis. Rheumatol Int. 2012;32:379–85.
Chen Q, Wei W. Effects and mechanisms of melatonin on inflammatory and immune responses of adjuvant arthritis rat. Int Immunopharmacol. 2002;2:1443–9.
Huang CC, Chiou CH, Liu SC, Hu SL, Su CM, Tsai CH, et al. Melatonin attenuates TNF-alpha and IL-1beta expression in synovial fibroblasts and diminishes cartilage degradation: implications for the treatment of rheumatoid arthritis. J Pineal Res. 2019;66:e12560.
Ayoub MA, Levoye A, Delagrange P, Jockers R. Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers. Mol Pharmacol. 2004;66:312–21.
Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351:152–66.
Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Res. 2006;66:9789–93.
Slominski AT, Zmijewski MA, Semak I, Kim TK, Janjetovic Z, Slominski RM, et al. Melatonin, mitochondria, and the skin. Cell Mol Life Sci. 2017;74:3913–25.
Yang YC, Chiou PC, Chen PC, Liu PY, Huang WC, Chao CC, et al. Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, beta-catenin, and twist pathways. Environ Toxicol. 2019;34:203–9.
Kim TK, Kleszczynski K, Janjetovic Z, Sweatman T, Lin Z, Li W, et al. Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells. FASEB J: Off Publ Federation Am Soc Exp Biol. 2013;27:2742–55.
Slominski AT, Semak I, Fischer TW, Kim TK, Kleszczynski K, Hardeland R, et al. Metabolism of melatonin in the skin: why is it important? Exp Dermatol. 2017;26:563–8.
Leja-Szpak A, Nawrot-Porabka K, Goralska M, Jastrzebska M, Link-Lenczowski P, Bonior J, et al. Melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine (afmk) enhance chemosensitivity to gemcitabine in pancreatic carcinoma cells (PANC-1). Pharmacol Rep. 2018;70:1079–88.
Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer. 1995;71:854–6.
Lissoni P, Meregalli S, Fossati V, Paolorossi F, Barni S, Tancini G, et al. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori. 1994;80:464–7.
Wang Y, Wang P, Zheng X, Du X. Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis. Onco Targets Ther. 2018;11:7895–908.
Menendez-Menendez J, Martinez-Campa C. Melatonin: an anti-tumor agent in hormone-dependent cancers. Int J Endocrinol. 2018;2018:3271948.
Palmer ACS, Zortea M, Souza A, Santos V, Biazus JV, Torres ILS, et al. Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: a randomized, double-blind, placebo-controlled trial. PLoS ONE. 2020;15:e0231379.
Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, et al. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012;11:293–303.
Farach-Carson MC, Lin SH, Nalty T, Satcher RL. Sex differences and bone metastases of breast, lung, and prostate cancers: do bone homing cancers favor feminized bone marrow? Front Oncol. 2017;7:163.
Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97:59–69.
Kozlow W, Guise TA. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J Mammary Gland Biol Neoplasia. 2005;10:169–80.
Rouach V, Goldshtein I, Wolf I, Catane R, Chodick G, Iton A, et al. Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer. J Bone Oncol. 2018;12:91–5.
Dauchy RT, Xiang S, Mao L, Brimer S, Wren MA, Yuan L, et al. Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer. Cancer Res. 2014;74:4099–110.
Hall CL, Bafico A, Dai J, Aaronson SA, Keller ET. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 2005;65:7554–60.
Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:6213s–6s.
Han Y, Kim YM, Kim HS, Lee KY. Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression. Sci Rep. 2017;7:5716.
Meng X, Zhu Y, Tao L, Zhao S, Qiu S. miR-590-3p mediates melatonin-induced cell apoptosis by targeting septin 7 in the human osteoblast cell line hFOB 1.19. Mol Med Rep. 2018;17:7202–8.
Liu JF, Chen CY, Chen HT, Chang CS, Tang CH. BL-038, a Benzofuran derivative, induces cell apoptosis in human chondrosarcoma cells through reactive oxygen species/mitochondrial dysfunction and the caspases dependent pathway. Int J Mol Sci. 2016;17:1491.
Lee HP, Wang SW, Wu YC, Tsai CH, Tsai FJ, Chung JG, et al. Glucocerebroside reduces endothelial progenitor cell-induced angiogenesis. Food Agr Immunol. 2019;30:1033–45.
Lee HP, Chen PC, Wang SW, Fong YC, Tsai CH, Tsai FJ, et al. Plumbagin suppresses endothelial progenitor cell-related angiogenesis in vitro and in vivo. J Funct Foods. 2019;52:537–44.
Lee HP, Wang SW, Wu YC, Lin LW, Tsai FJ, Yang JS, et al. Soya-cerebroside inhibits VEGF-facilitated angiogenesis in endothelial progenitor cells. Food Agr Immunol. 2020;31:193–204.
Wu MH, Lo JF, Kuo CH, Lin JA, Lin YM, Chen LM, et al. Endothelin-1 promotes MMP-13 production and migration in human chondrosarcoma cells through FAK/PI3K/Akt/mTOR pathways. J Cell Physiol. 2012;227:3016–26.
Wang M, Chao CC, Chen PC, Liu PI, Yang YC, Su CM, et al. Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis. Biochem Pharmacol. 2019;166:23–32.
Chuang JY, Chang AC, Chiang IP, Tsai MH, Tang CH. Apoptosis signal-regulating kinase 1 is involved in WISP-1-promoted cell motility in human oral squamous cell carcinoma cells. PloS ONE. 2013;8:e78022.
Chen PC, Cheng HC, Tang CH. CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway. Carcinogenesis. 2013;34:1669–79.
Chang AC, Chen PC, Lin YF, Su CM, Liu JF, Lin TH, et al. Osteoblast-secreted WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/integrin alpha4beta1 system. Cancer Lett. 2018;426:47–56.
We would like to thank Iona J. MacDonald from China Medical University for her English language revision of this paper.
This study was supported by grants from Taiwan’s Ministry of Science and Technology (MOST 108-2320-B-039-026-, MOST 109-2320-B-341-002-), China Medical University Hospital (DMR-110-102), Shin Kong Wu Ho-Su Memorial Hospital (2020SKHBND001), China Medical University under the Higher Education Sprout Project, Ministry of Education, Taiwan (CMRC-CHM-3-1), Asia University Hospital (10951002) and Chung Shan Medical University Hospital, Taiwan (CSH-2020-E-001-Y3).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Liu, PI., Chang, AC., Lai, JL. et al. Melatonin interrupts osteoclast functioning and suppresses tumor-secreted RANKL expression: implications for bone metastases. Oncogene 40, 1503–1515 (2021). https://doi.org/10.1038/s41388-020-01613-4