Causal effects of serum trace elements and nutrients on osteonecrosis: a Mendelian randomization analysis

doi:10.12307/2024.654

Abstract

Abstract: BACKGROUND: Multiple clinical observational studies have suggested a close relationship of serum trace elements and nutrients with osteonecrosis, but it remains unclear whether there is a genetic causal effect between serum trace elements and nutrients on osteonecrosis.
OBJECTIVE: To investigate the causal effects of serum trace elements and nutrients on osteonecrosis using the Mendelian randomization approach.
METHODS: The exposure factors of serum trace elements and vitamins with mononucleotide polymorphisms were obtained from the published UK Biobank database and publicly available databases of genome-wide association studies. The outcome event of osteonecrosis was derived from the FinnGen Biobank database. Mendelian randomization methods were employed to explore the causal relationship between seven trace elements and three nutrients with osteonecrosis. Causal inference was conducted using inverse variance weighting, MR-Egger, and weighted median methods. F-statistic was calculated to ensure the robustness of instrumental variables. Cochran's Q test and leave-one-out method were used for heterogeneity testing. MR-Egger regression and MR-PRESSO were employed for horizontal pleiotropy testing. PhenoScanner database was utilized to remove mononucleotide polymorphisms with horizontal pleiotropy to ensure the reliability of the results.
RESULTS AND CONCLUSION: Causal relationships were found between serum selenium, phosphate, vitamin C, vitamin E, and osteonecrosis through Mendelian randomization analysis. Serum selenium, vitamin C, and vitamin E were found to have a protective effect on osteonecrosis, while excessive intake of phosphate increased the risk of osteonecrosis. No heterogeneity or horizontal pleiotropy was observed during the study, and Mendelian randomization statistical power (Power value > 80%) indicated the reliability of the aforementioned four results. These findings have important clinical implications for the development of targeted preventive and therapeutic measures for osteonecrosis.

Key words: Mendelian randomization, trace element, nutrient, osteonecrosis, single nucleotide polymorphism, inverse variance weighted method

CLC Number:

Liu Yi, Liu Yuan, Liu Jinbao, Li Nianhu, Zhu Weiming, Xu Bo. Causal effects of serum trace elements and nutrients on osteonecrosis: a Mendelian randomization analysis[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(33): 5326-5332.

Figures/Tables 7

References

[1] JONES LC, HUNGERFORD DS. Osteonecrosis: etiology, diagnosis, and treatment. Curr Opin Rheumatol. 2004;16(4):443-449.
[2] WU X, SUN W, TAN M. Noncoding RNAs in Steroid-Induced Osteonecrosis of the Femoral Head. Biomed Res Int. 2019;2019: 8140595.
[3] WELDON D. The effects of corticosteroids on bone: osteonecrosis (avascular necrosis of the bone). Ann Allergy Asthma Immunol. 2009; 103(2):91-133.
[4] LIU Y, MO L, LU H, et al. Dragon blood resin ameliorates steroid-induced osteonecrosis of femoral head through osteoclastic pathways. Front Cell Dev Biol. 2023;11:1202888.
[5] CHAI JL, LU BW, DU HT, et al. Pyroptosis -related potential diagnostic biomarkers in steroid-induced osteonecrosis of the femoral head. BMC Musculoskelet Disord. 2023;24(1):609.
[6] KONARSKI W, POBOŻY T, KONARSKA K, et al. Osteonecrosis Related to Steroid and Alcohol Use-An Update on Pathogenesis. Healthcare (Basel). 2023;11(13):1846.
[7] YAMAMOTO T, IWAMOTO Y. Corticosteroids treatments and osteonecrosis of the femoral head. Fukuoka Igaku Zasshi. 2015;106(3):47-53.
[8] WEINSTEIN RS. Glucocorticoid-induced osteonecrosis. Endocrine. 2012;41(2):183-190.
[9] PAVELKA K. Osteonecrosis. Baillieres Best Pract Res Clin Rheumatol. 2000;14(2):399-414.
[10] ZOFKOVÁ I, NEMCIKOVA P, MATUCHA P. Trace elements and bone health. Clin Chem Lab Med. 2013;51(8):1555-1561.
[11] MILACHOWSKI KA. Investigation of ischaemic necrosis of the femoral head with trace elements. Int Orthop. 1988;12(4):323-330.
[12] WANG L, ZHANG L, GAO M. Metabolic Disorders and Mineral Density of the Bone Tissue in the Early Pathogenesis of Osteonecrosis: Study on Rabbits with Steroid-Induced Osteonecrosis. Bull Exp Biol Med. 2021;170(6):724-728.
[13] ZHENG LZ, WANG JL, XU JK, et al. Magnesium and vitamin C supplementation attenuates steroid-associated osteonecrosis in a rat model. Biomaterials. 2020;238:119828.
[14] BOCANEGRA-PÉREZ MS, VICENTE-BARRERO M, SOSA-HENRÍQUEZ M, et al. Bone metabolism and clinical study of 44 patients with bisphosphonate-related osteonecrosis of the jaws. Med Oral Patol Oral Cir Bucal. 2012;17(6):e948-e955.
[15] LORENZO-POUSO AI, PÉREZ-SAYÁNS M, GARCÍA A, et al. Vitamin D supplementation: Hypothetical effect on medication-related osteonecrosis of the jaw. Med Hypotheses. 2018;116:79-83.
[16] YANG J, WU W, AMIER Y, et al. Causal relationship of genetically predicted circulating micronutrients levels with the risk of kidney stone disease: a Mendelian randomization study. Front Nutr. 2023;10: 1132597.
[17] ZHU RC, LI FF, WU YQ, et al. Minimal effect of sleep on the risk of age-related macular degeneration: a Mendelian randomization study. Front Aging Neurosci. 2023;15:1159711.
[18] DI RESTA C, PIPITONE GB, CARRERA P, et al. Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing. Neural Regen Res. 2021;16(3):475-481
[19] ZHONG X, WANG L, XU L, et al. Disturbance of skin sensation and autism spectrum disorder: A bidirectional Mendelian randomization study. Brain Behav. 2023:e3238. doi: 10.1002/brb3.3238.
[20] SKRIVANKOVA VW, RICHMOND RC, WOOLF BAR, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021; 326(16):1614-1621.
[21] 熊海安,刘晓玲,白植宝.上颌骨双磷酸盐相关性骨坏死临床观察[J].青海医药杂志,2020,50(5):74-76.
[22] ENDO T, FUNAYAMA H, YAMAGUCHI K, et al. Basic studies on the mechanism, prevention, and treatment of osteonecrosis of the jaw induced by bisphosphonates. Yakugaku Zasshi. 2020;140(1):63-79.
[23] MÜLLER WEG, ACKERMANN M, AL-NAWAS B, et al. Amplified morphogenetic and bone forming activity of amorphous versus crystalline calcium phosphate/polyphosphate. Acta Biomater. 2020; 118:233-247.
[24] HUGHES EAB, ROBINSON TE, BASSETT DB, et al. Critical and diverse roles of phosphates in human bone formation. J Mater Chem B. 2019; 7(47):7460-7470.
[25] PAZARÇEVIREN AE, TEZCANER A, KESKIN D, et al. Boron-doped Biphasic Hydroxyapatite/β-Tricalcium Phosphate for Bone Tissue Engineering. Biol Trace Elem Res. 2021;199(3):968-980.
[26] THOMAS J, WORCH H, KRUPPKE B, et al. Contribution to understand the biomineralization of bones. J Bone Miner Metab. 2020;38(4):456-468.
[27] GILBERT AK, NEWTON TD, HETTIARATCHI MH, et al. Reactive sulfur and selenium species in the regulation of bone homeostasis. Free Radic Biol Med. 2022;190:148-157.
[28] WANG N, XIE D, WU J, et al. Selenium and bone health: a protocol for a systematic review and meta-analysis. BMJ Open. 2020;10(10):e036612.
[29] 胡一新,石小兵,谢润琪,等.绝经后女性血清硒水平与骨质疏松骨密度和骨代谢指标相关性研究[J].中国骨质疏松杂志,2021, 27(9):1329-1332.
[30] KURIBAYASHI M, FUJIOKA M, TAKAHASHI KA, et al. Vitamin E prevents steroid-induced osteonecrosis in rabbits. Acta Orthop. 2010;81(1): 154-160.
[31] AGHAJANIAN P, HALL S, WONGWORAWAT MD, et al. The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments. J Bone Miner Res. 2015;30(11):1945-1955.
[32] REID IR. Nutrition and bone health: the case of selenium. Lancet Healthy Longev. 2021;2(4):e185-e186.
[33] YANG T, LEE SY, PARK KC, et al. The Effects of Selenium on Bone Health: From Element to Therapeutics. Molecules. 2022;27(2):392.
[34] DENG H, LIU H, YANG Z, et al. Progress of Selenium Deficiency in the Pathogenesis of Arthropathies and Selenium Supplement for Their Treatment. Biol Trace Elem Res. 2022;200(10):4238-4249.
[35] YAZICI T, KOÇER G, NAZIROĞLU M, et al. Zoledronic Acid, Bevacizumab and Dexamethasone-Induced Apoptosis, Mitochondrial Oxidative Stress, and Calcium Signaling Are Decreased in Human Osteoblast-Like Cell Line by Selenium Treatment. Biol Trace Elem Res. 2018;184(2):358-368.
[36] WONG SK, MOHAMAD NV, IBRAHIM N’, et al. The Molecular Mechanism of Vitamin E as a Bone-Protecting Agent: A Review on Current Evidence. Int J Mol Sci. 2019;20(6):1453.
[37] GHARANIZADEH K, AMINIZADEH S, MOLAVI N, et al. Effects of Zoledronic Acid and Vitamin E on Surgical- Induced Osteonecrosis of the Femoral Head in Rabbit. Arch Bone Jt Surg. 2018;6(6):547-553.
[38] JIA YB, JIANG DM, REN YZ, et al. Inhibitory effects of vitamin E on osteocyte apoptosis and DNA oxidative damage in bone marrow hemopoietic cells at early stage of steroid-induced femoral head necrosis. Mol Med Rep. 2017;15(4):1585-1592.