Bone-protective effects of melatonin in ovariectomized rats: insights from histomorphometry

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DOI:

https://doi.org/10.5902/2236583493537

Keywords:

Melatonin, Histomorphometry, Hypoestrogenism, Menopause, Wistar rats

Abstract

Objective: To evaluate the effects of melatonin on structural and remodeling parameters in tibiae of ovariectomized (OVX) and sham-operated (SHAM) female rats. Methods: Sixty female Wistar rats underwent OVX (n=30) or SHAM surgery (n=30) at 20 weeks of age. After surgery, each group was divided into three subgroups (n=10) that received melatonin at 20 mg/kg, 50 mg/kg, or placebo via oral gavage for 8 weeks, starting 12 weeks post-surgery. At 40 weeks of age tibiae were collected for histomorphometric analysis. Results: Both 20 mg/kg and 50 mg/kg doses maintained bone volume fraction (BV/TV). The 50 mg/kg dose preserved trabecular number (Tb.N), trabecular separation (Tb.Sp),   and significantly decreased eroded surface (ES/BS), indicating preserved bone microarchitecture and reduced resorption. In SHAM rats, melatonin at 50 mg/kg also reduced ES/BS. No correlation was found between body weight and bone parameters. HbA1c levels were significantly lower in OVX rats treated with melatonin at both doses. No significant changes were observed in other biochemical markers or CTX levels. Conclusion: Melatonin, particularly at 50 mg/kg, significantly preserves bone  microarchitecture and attenuates bone loss in OVX rats. Its limited effect in SHAM rats underscores its efficacy under hypoestrogenic conditions. These findings highlight the potential of melatonin as a therapeutic agent for menopause-related bone loss and metabolic complications, supporting further translational research.

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Author Biographies

Fatima Sandmann Afonso, Universidade Federal do Paraná

Master's degree in Internal Medicine from the Federal University of Paraná.

Rafaela Ceron, Laboratório de Patologia Renal e Óssea do Instituto Pró Renal

Biomedical from the Tuiuti University of Paraná.

Angela Maria Reck, Universidade Positivo

Master in Veterinary Sciences from the State University of the Central-West.

Leticia Capote dos Santos, Universidade Tuiuti

Postgraduate degree in endodontics from the Dental Institute of the Americas - IOA Boutique.

Lorena Bavia, Universidade Federal do Paraná

PhD in Immunology from the University of São Paulo.

Maritana Mela Prodocimo, Universidade Federal do Paraná

PhD in Neuroscience and Behavior from the University of São Paulo.

Liliane Roskamp, Universidade Tuiuti

PhD in Dentistry from the Pontifical Catholic University of Paraná.

Thais Andrade Costa Casagrande, Universidade Positivo

PhD in Science from the Faculty of Veterinary Medicine and Animal Science at the University of São Paulo.

Vicente Florentino Castaldo Andrade, Universidade Federal do Paraná

PhD in Internal Medicine from the Federal University of Paraná.

Carolina Aguiar Moreira, Laboratório de Patologia Renal e Óssea do Instituto Pró Renal

PhD in Internal Medicine from the Federal University of Paraná.

References

Amaral FG, Cipolla-Neto J. A brief review about melatonin, a pineal hormone. Arch Endocrinol Metab. 2018;62:472–9. doi: 10.20945/2359-3997000000066

Xie Z, et al. A review of sleep disorders and melatonin. Neurol Res. 2017; 39:559–65. doi: 10.1080/01616412.2017.1315864.

Cipolla-Neto J, Do Amaral FG. Melatonin as a hormone: new physiological and clinical insights. Endocr Rev. 2018;39:990–1028. doi: 10.1210/er.2018-00084.

Goldman BD. Mammalian photoperiodic system: formal properties and neuroendocrine mechanisms of photoperiodic time measurement. J Biol Rhythms. 2001;16:283–301. doi: 10.1177/074873001129001980.

Ahmad SB, et al. Melatonin and health: insights of melatonin action, biological functions, and associated disorders. Cell Mol Neurobiol. 2023;43:2437–58. doi:10.1007/s10571-023-01324-w.

Hendrickx G, Boudin E, Van Hul W. A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol. 2015;11:462–74. doi: 10.1038/nrrheum.2015.48.

Li T, et al. Melatonin: another avenue for treating osteoporosis? J Pineal Res. 2019;66:e12548. doi:10.1111/jpi.12548.

Guan H, et al. Melatonin increases bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats via the promotion of osteogenesis. J Transl Med. 2022;20:132. doi:10.1186/s12967-022-03341-7.

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. doi:10.3390/ijms18061142.

Zhou L, et al. Melatonin at pharmacological concentrations suppresses osteoclastogenesis via the attenuation of intracellular ROS Osteoporos Int. 2017;28:3325–37. doi: 10.1007/s00198 017 4129 y.

Ikegame M, et al. Melatonin is a potential drug for the prevention of bone loss during space flight. J Pineal Res. 2019;67:e12594. doi:10.1111/jpi.12594.

Ladizesky MG, et al. Effect of melatonin on bone metabolism in ovariectomized rats. Life Sci. 2001;70:557–65. doi: 10.1016/S0024-3205(01)01431-X.

Munmun F, Witt-Enderby PA. Melatonin effects on bone: implications for use as a therapy for managing bone loss. J Pineal Res. 2021;71:e12749. doi:10.1111/jpi.12749.

Chavassieux P, Chapurlat R. Interest of bone histomorphometry in bone pathophysiology investigation: foundation, present, and future Front Endocrinol (Lausanne). 2022;13:907914. doi:10.3389/fendo.2022.907914.

Eriksen EF, et al. Modeling-based bone formation after 2 months of Romosozumab treatment: results from the FRAME clinical trial. J Bone Miner Res. 2022;37:36–40. doi: 10.1002/jbmr.4457.

Tresguerres IF, et al. Melatonin dietary supplement as an anti-aging therapy for age-related bone loss. Rejuvenation Res. 2014;17:341–6. doi: 10.1089/rej.2013.1542.

Sharan K, Lewis K, Furukawa T, Yadav VK. Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway. J Pineal Res. 2017;63:e12423. doi:10.1111/jpi.12423.

Dempster DW, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013; 28:2–17. doi:10.1002/jbmr.1805.

Baxi DB, Singh PK, Vachhrajani KD, Ramachandran AV. Melatonin supplementation in rat ameliorates ovariectomy-induced oxidative stress. Climacteric. 2013;16:274–83. doi: 10.3109/13697137.2012.682108.

Monteiro P, et al. A glândula pineal e o metabolismo de carboidratos. Arq Bras Endocrinol Metab. 2000;44(4):349–59. doi:10.1590/S0004-27302000000400009.

Garaulet M, et al. Melatonin effects on glucose metabolism: time to unlock the controversy. Trends Endocrinol Metab. 2020;31:192–204. doi:10.1016/j.tem.2019.11.011.

Li T, et al. Daytime administration of melatonin has better protective effects on bone loss in ovariectomized rats. J Orthop Surg Res. 2023;18:234. doi:10.1186/s13018-023-03695-8.

Huang X, et al. Melatonin suppresses bone marrow adiposity in ovariectomized rats by rescuing the imbalance between osteogenesis and adipogenesis through SIRT1 activation. J Orthop Translat. 2023;38:84–97. doi: 10.1016/j.jot.2022.10.002

Zhou MS, et al. Systemic administration with melatonin in the daytime has a better effect on promoting osseointegration of titanium rods in ovariectomized rats. Bone Joint Res. 2022;11:751–62. doi: 10.1302/2046-3758.1111.BJR-2022-0017.R2.

Chu ZM, et al. Melatonin promotes osteoblast differentiation of bone marrow mesenchymal stem cells in aged rats. Eur Rev Med Pharmacol Sci. 2017; 21:4446–56.

Zheng S, et al. Melatonin accelerates osteoporotic bone defect repair by promoting osteogenesis–angiogenesis coupling. Front Endocrinol (Lausanne). 2022;13:826660. doi:10.3389/fendo.2022.82666.

Pejon TMM, et al. Melatonin administration on bone properties of animals under hypoestrogenism: a systematic review. Rev Endocr Metab Disord. 2025; 26: 279-291. doi:10.1007/s11154-025-09953-w.

Chen W, et al. Melatonin improves the resistance of oxidative stress-induced cellular senescence in osteoporotic bone marrow mesenchymal stem cells. Oxid Med Cell Longev. 2022. Jan 18;2022: 7420726. doi: 10.1155/2022/7420726.

Schini M, Vilaca T, Gossiel F, Salam S, Eastell R. Bone turnover markers: basic biology to clinical applications. Endocr Rev. 2023;44:417–73. doi:10.1210/endrev/bnac031.

Hlaing TT, Compston JE. Biochemical markers of bone turnover – uses and limitations. Ann Clin Biochem. 2014;51:189–202. doi:10.1177/0004563213515190.

Brown JP, Don-Wauchope A, Douville P, Albert C, Vasikaran SD. Current use of bone turnover markers in the management of osteoporosis. Clin Biochem. 2022;109–110:1–10. doi:10.1016/j.clinbiochem.2022.09.002.

Guo X, Yu X, Yao Q, Qin J. Early effects of ovariectomy on bone microstructure, bone turnover markers and mechanical properties in rats. BMC Musculoskelet Disord. 2022; 23. doi: 10.1186/s12891-022-05265-1.

Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol (Lausanne). 2022;13:839005. doi:10.3389/fendo.2022.839005.

Cardinali DP. Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved. J Pineal Res. 2024;76:e12931. doi:10.1111/jpi.12931.

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Published

2025-09-04

How to Cite

Afonso, F. S., Ceron, R., Reck, A. M., Santos, L. C. dos, Bavia, L., Prodocimo, M. M., Roskamp, L., Casagrande, T. A. C., Andrade, V. F. C., & Moreira, C. A. (2025). Bone-protective effects of melatonin in ovariectomized rats: insights from histomorphometry. Saúde (Santa Maria), 51, e93537. https://doi.org/10.5902/2236583493537

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