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Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.4 P.301-311


Iron accumulation and its impact on osteoporotic fractures in postmenopausal women

Author(s):  Hui CAI, Huimei ZHANG, Weiting HE, Heng ZHANG

Affiliation(s):  Department of Pharmacy, the First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233004, China; more

Corresponding email(s):   bygkzhangheng@163.com

Key Words:  Iron accumulation, Postmenopausal osteoporosis, Bone metabolism, Osteoporotic fracture

Hui CAI, Huimei ZHANG, Weiting HE, Heng ZHANG. Iron accumulation and its impact on osteoporotic fractures in postmenopausal women[J]. Journal of Zhejiang University Science B, 2023, 24(4): 301-311.

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author="Hui CAI, Huimei ZHANG, Weiting HE, Heng ZHANG",
journal="Journal of Zhejiang University Science B",
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%T Iron accumulation and its impact on osteoporotic fractures in postmenopausal women
%A Hui CAI
%A Huimei ZHANG
%A Weiting HE
%J Journal of Zhejiang University SCIENCE B
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%DOI 10.1631/jzus.B2200519

T1 - Iron accumulation and its impact on osteoporotic fractures in postmenopausal women
A1 - Hui CAI
A1 - Huimei ZHANG
A1 - Weiting HE
A1 - Heng ZHANG
J0 - Journal of Zhejiang University Science B
VL - 24
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B2200519

postmenopausal osteoporosis is a kind of degenerative disease, also described as “invisible killer.” Estrogen is generally considered as the key hormone for women to maintain bone mineral content during their lives. iron accumulation refers to a state of human serum ferritin that is higher than the normal value but less than 1000 μg/L. It has been found that iron accumulation and osteoporosis could occur simultaneously with the decrease in estrogen level after menopause. In recent years, many studies indicated that iron accumulation plays a vital role in postmenopausal osteoporosis, and a significant correlation has been found between iron accumulation and fragility fractures. In this review, we summarize and analyze the relevant literature including randomized controlled trials, systematic reviews, and meta-analyses between January 1996 and July 2022. We investigate the mechanism of the effect of iron accumulation on bone metabolism and discuss the relationship of iron accumulation, osteoporosis, and postmenopausal fragility fractures, as well as the main clinical treatment strategies. We conclude that it is necessary to pay attention to the phenomenon of iron accumulation in postmenopausal women with osteoporosis and explore the in-depth mechanism of abnormal bone metabolism caused by iron accumulation, in order to facilitate the discovery of effective therapeutic targets for postmenopausal osteoporosis.


概要:绝经后骨质疏松症是一种发生于骨骼的退行性疾病,号称"隐形杀手"。雌激素是女性一生中维持骨矿物质含量的关键激素。铁蓄积是指人血清铁蛋白高于正常值但低于1000 µg/L的状态。研究发现,绝经后随着雌激素水平的降低,铁蓄积和骨质疏松症可同时发生。近年来,很多研究表明铁蓄积在绝经后骨质疏松症发生中起着至关重要的作用,且铁蓄积与骨质疏松性骨折也有显著的相关性。在本文中,我们对1996年1月至2022年7月期间的随机对照试验、系统综述和荟萃分析等相关文献进行了总结和分析,探讨铁蓄积对骨代谢影响的机制,阐明铁蓄积与骨质疏松、绝经后脆性骨折的关系及临床主要治疗策略。我们总结认为,有必要关注女性绝经后骨质疏松铁蓄积现象。深入探讨铁蓄积引起骨代谢异常的机制,有助于发现绝经后骨质疏松有效的治疗靶点。


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]AnthamattenA, ParishA, 2019. Clinical update on osteoporosis. J Midwifery Womens Health, 64(3):265-275.

[2]BaloghE, TolnaiE, NagyB, et al., 2016. Iron overload inhibits osteogenic commitment and differentiation of mesenchymal stem cells via the induction of ferritin. Biochim Biophys Acta (BBA) Mol Basis Dis, 1862(9):1640-1649.

[3]BaloghE, ParaghG, JeneyV, 2018. Influence of iron on bone homeostasis. Pharmaceuticals, 11(4):107.

[4]CamaschellaC, NaiA, SilvestriL, 2020. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica, 105(2):260-272.

[5]Carrillo-LópezN, Martínez-AriasL, Fernández-VillabrilleS, et al., 2021. Role of the RANK/RANKL/OPG and Wnt/β‍-catenin systems in CKD bone and cardiovascular disorders. Calcif Tissue Int, 108(4):439-451.

[6]CheJM, LvHH, YangJC, et al., 2021. Iron overload induces apoptosis of osteoblast cells via eliciting ER stress-mediated mitochondrial dysfunction and p-eIF2α/ATF4/CHOP pathway in vitro. Cell Signal, 84:110024.

[7]ChenB, LiGF, ShenY, et al., 2015. Reducing iron accumulation: a potential approach for the prevention and treatment of postmenopausal osteoporosis. Exp Ther Med, 10(1):‍7-11.

[8]ChenYT, LinLM, WangXD, et al., 2022. Effect of Lingnan Chen’s acupuncture on postmenopausal osteoporosis and serum GH and IGF-1. Chin Acupunct Moxibust, 42(9):979-984 (in Chinese).

[9]CheungWH, SunMH, ZhengYP, et al., 2012. Stimulated angiogenesis for fracture healing augmented by low-magnitude, high-frequency vibration in a rat model-evaluation of pulsed-wave Doppler, 3-D power Doppler ultrasonography and micro-CT microangiography. Ultrasound Med Biol, 38(12):2120-2129.

[10]DiomedeF, MarconiGD, FonticoliL, et al., 2020. Functional relationship between osteogenesis and angiogenesis in tissue regeneration. Int J Mol Sci, 21(9):3242.

[11]DoyardM, FatihN, MonnierA, et al., 2012. Iron excess limits HHIPL-2 gene expression and decreases osteoblastic activity in human MG-63 cells. Osteoporos Int, 23(10):2435-2445.

[12]ErberL, LiuS, GongY, et al., 2022. Quantitative proteome and transcriptome dynamics analysis reveals iron deficiency response networks and signature in neuronal cells. Molecules, 27(2):484.

[13]FanLH, LiJ, YuZF, et al., 2014. The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration. Biomed Res Int, 2014:239356.

[14]FiedlerJ, RödererG, GüntherKP, et al., 2002. BMP-2, BMP-4, and PDGF-bb stimulate chemotactic migration of primary human mesenchymal progenitor cells. J Cell Biochem, 87(3):‍305-312.

[15]FilipowskaJ, TomaszewskiKA, NiedźwiedzkiŁ, et al., 2017. The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis, 20(3):291-302.

[16]FungEB, HarmatzPR, MiletM, et al., 2008. Fracture prevalence and relationship to endocrinopathy in iron overloaded patients with sickle cell disease and thalassemia. Bone, 43(1):162-168.

[17]Gaffney-StombergE, 2019. The impact of trace minerals on bone metabolism. Biol Trace Elem Res, 188:26-34.

[18]GinzburgYZ, 2019. Hepcidin-ferroportin axis in health and disease. Vitam Horm, 110:17-45.

[19]HamadM, BajboujK, TaneeraJ, 2020. The case for an estrogen-iron axis in health and disease. Exp Clin Endocrinol Diabetes, 128(4):270-277.

[20]HangHF, DongLJ, TangXB, et al., 2020. Bone microthrombus promotes bone loss in iron accumulation rats. Curr Med Sci, 40(5):943-950.

[21]HeCY, WangZ, ShiJS, 2020. Pharmacological effects of icariin. Adv Pharmacol, 87:179-203.

[22]HsuCC, SenussiNH, FertrinKY, et al., 2022. Iron overload disorders. Hepatol Commun, 6(8):1842-1854.

[23]HuangX, 2015. Treatment of osteoporosis in peri-and post-menopausal women with hepcidin. US Patent 8999935.

[24]HuoJ, SunX, 2016. Effect of Astragalus polysaccharides on ovariectomy-induced osteoporosis in mice. Genet Mol Res, 15(4):gmr15049169.

[25]JandialR, ChenMY, CiacciJ, 2011. HIF-1α potentiates mesenchymal stem cell mediated osteogenesis by coupling to angiogenesis. Neurosurgery, 69(4):N13-N14.

[26]JianJL, PelleE, HuangX, 2009. Iron and menopause: does increased iron affect the health of postmenopausal women? Antioxid Redox Signal, 11(12):2939-2943.

[27]JiangY, ChenB, YanYL, et al., 2019. Hepcidin protects against iron overload-induced inhibition of bone formation in zebrafish. Fish Physiol Biochem, 45(1):365-374.

[28]JingXZ, DuT, ChenK, et al., 2019. Icariin protects against iron overload-induced bone loss via suppressing oxidative stress. J Cell Physiol, 234(7):10123-10137.

[29]JorgensenC, KhouryM, 2021. Musculoskeletal progenitor/stromal cell-derived mitochondria modulate cell differentiation and therapeutical function. Front Immunol, 12:606781.

[30]KeJY, CenWJ, ZhouXZ, et al., 2017. Iron overload induces apoptosis of murine preosteoblast cells via ROS and inhibition of AKT pathway. Oral Dis, 23(6):784-794.

[31]KimBJ, LeeSH, KohJM, et al., 2013. The association between higher serum ferritin level and lower bone mineral density is prominent in women ≥45 years of age (KNHANES 2008-2010). Osteoporos Int, 24(10):2627-2637.

[32]KirD, SalujaM, ModiS, et al., 2016. Cell-permeable iron inhibits vascular endothelial growth factor receptor-2 signaling and tumor angiogenesis. Oncotarget, 7(40):‍65348-65363.

[33]KobayakawaT, MiyazakiA, SaitoM, et al., 2021. Denosumab versus romosozumab for postmenopausal osteoporosis treatment. Sci Rep, 11:11801.

[34]KodamaJ, KaitoT, 2020. Osteoclast multinucleation: review of current literature. Int J Mol Sci, 21(16):5685.

[35]KomoriT, YagiH, NomuraS, et al., 1997. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell, 89(5):755-764.

[36]KusumbeAP, RamasamySK, AdamsRH, 2014. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature, 507(7492):323-328.

[37]LederBZ, 2017. Parathyroid hormone and parathyroid hormone-related protein analogs in osteoporosis therapy. Curr Osteoporos Rep, 15(2):110-119.

[38]LiangWQ, ZhongC, LiYM, 2020. Overview of etiology and pathogenesis and advance in the treatment of osteoporosis in Chinese medicine. Chin J Osteoporos, 26(1):‍135-139 (in Chinese).

[39]LiuF, ZhangWL, MengHZ, et al., 2017. Regulation of DMT1 on autophagy and apoptosis in osteoblast. Int J Med Sci, 14(3):275-283.

[40]LiuH, WangYW, ChenWD, et al., 2021. Iron accumulation regulates osteoblast apoptosis through lncRNA XIST/miR-758-3p/caspase 3 axis leading to osteoporosis. IUBMB Life, 73(2):432-443.

[41]LiuLL, LiuGW, LiuH, et al., 2021. Iron accumulation deteriorated bone loss in estrogen-deficient rats. J Orthop Surg Res, 16:525.

[42]LuHD, LianLY, ShiDH, et al., 2015. Hepcidin promotes osteogenic differentiation through the bone morphogenetic protein 2/small mothers against decapentaplegic and mitogen-activated protein kinase/P38 signaling pathways in mesenchymal stem cells. Mol Med Rep, 11(1):‍143-150.

[43]MaHY, ChenS, LuLL, et al., 2021. Raloxifene in the treatment of osteoporosis in postmenopausal women with end-stage renal disease: a systematic review and meta-analysis. Horm Metab Res, 53(11):730-737.

[44]MeiM, XiangZJ, YangJH, et al., 2020. Efficacy of zoledronic acid for prevention of bone loss in early-stage breast cancer patients receiving adjuvant therapy: a meta-analysis of 13 randomized controlled trials. Curr Probl Cancer, 44(2):100507.

[45]NemethE, GanzT, 2021. Hepcidin-ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci, 22(12):6493.

[46]OttoF, ThornellAP, CromptonT, et al., 1997. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell, 89(5):765-771.

[47]OuL, WeiPF, LiM, et al., 2019. Inhibitory effect of Astragalus polysaccharide on osteoporosis in ovariectomized rats by regulating FoxO3a /Wnt signaling pathway. Acta Cir Bras, 34(5):e201900502.

[48]PapapoulosS, BoneH, CosmanF, et al., 2021. Incidence of hip and subtrochanteric/femoral shaft fractures in postmenopausal women with osteoporosis in the phase 3 long-term odanacatib fracture trial. J Bone Miner Res, 36(7):1225-1234.

[49]RoodmanGD, 2009. Osteoclasts pump iron. Cell Metab, 9(5):405-406.

[50]RozenbergS, Al-DaghriN, Aubertin-LeheudreM, et al., 2020. Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis? Osteoporos Int, 31(12):2271-2286.

[51]SimonetWS, LaceyDL, DunstanCR, et al., 1997. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell, 89(2):309-319.

[52]TangY, WuXW, LeiWQ, et al., 2009. TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med, 15(7):757-765.

[53]TianQ, WuSL, DaiZP, et al., 2016. Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway. PeerJ, 4:e2611.

[54]UdagawaN, KoideM, NakamuraM, et al., 2021. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab, 39(1):19-26.

[55]WangAF, XuYJ, 2022. Influence of iron accumulation on postmenopausal osteoporosis. Chin J Osteoporos Bone Miner Res, 15(3):225-231 (in Chinese).

[56]WangL, ZhouF, ZhangP, et al., 2017. Human type H vessels are a sensitive biomarker of bone mass. Cell Death Dis, 8(5):e2760.

[57]WangX, ChenB, SunJY, et al., 2018. Iron-induced oxidative stress stimulates osteoclast differentiation via NF-κB signaling pathway in mouse model. Metabolism, 83:167-176.

[58]XuGP, LiX, ZhuZY, et al., 2021. Iron overload induces apoptosis and cytoprotective autophagy regulated by ROS generation in Mc3t3-E1 cells. Biol Trace Elem Res, 199(10):3781-3792.

[59]XuYJ, LiGF, DuBC, et al., 2011. Hepcidin increases intracellular Ca2+ of osteoblast hFOB1.19 through L-type Ca2+ channels. Regul Pept, 172(1-3):58-61.

[60]YangF, YanGG, LiY, et al., 2016. Astragalus polysaccharide attenuated iron overload-induced dysfunction of mesenchymal stem cells via suppressing mitochondrial ROS. Cell Physiol Biochem, 39(4):1369-1379.

[61]YangQ, JianJL, AbramsonSB, et al., 2011. Inhibitory effects of iron on bone morphogenetic protein 2-induced osteoblastogenesis. J Bone Miner Res, 26(6):1188-1196.

[62]YuanY, XuF, CaoY, et al., 2019. Iron accumulation leads to bone loss by inducing mesenchymal stem cell apoptosis through the activation of caspase3. Biol Trace Elem Res, 187(2):434-441.

[63]ZarjouA, JeneyV, ArosioP, et al., 2010. Ferritin ferroxidase activity: a potent inhibitor of osteogenesis. J Bone Miner Res, 25(1):164-172.

[64]ZhangDW, ChengY, WangNL, et al., 2008. Effects of total flavonoids and flavonol glycosides from Epimedium koreanum Nakai on the proliferation and differentiation of primary osteoblasts. Phytomedicine, 15(1-2):55-61.

[65]ZhangP, WangS, WangL, et al., 2018. Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels. J Mol Endocrinol, 60(4):299-308.

[66]ZhangYQ, WangXD, WuQ, et al., 2018. Adenine alleviates iron overload by cAMP/PKA mediated hepatic hepcidin in mice. J Cell Physiol, 233(9):7268-7278.

[67]ZhuangHF, WangPW, LiYZ, et al., 2020. Analysis of related factors of brittle hip fracture in postmenopausal women with osteoporosis. Orthop Surg, 12(1):194-198.

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