Abstract
Zinc (Zn), copper (Cu), and iron (Fe) are essential trace elements for the growth, development, and maintenance of healthy bones. However, there are conflicting reports as to the relationship between serum level of Zn, Cu, or Fe and osteoporosis (OP). The purpose of the present study is to clarify the relationship between serum Zn, Cu, or Fe and OP using a meta-analysis approach. We searched all articles indexed in PubMed published up to May 2014 concerning the association between serum level of Zn, Cu, or Fe and OP. Eight eligible articles involving 2,188 subjects were identified. Overall, pooled analysis indicated that patients with OP had a lower serum level of Zn, Cu, or Fe than the healthy controls (Zn standardized mean difference (SMD) = −1.396, 95 % confidence interval (CI) = [−2.129, −0.663]; Cu SMD = −0.386, 95 % CI = [−0.538, −0.234]; Fe SMD = −0.22, 95 % CI = [−0.30, −0.13]). Further subgroup analysis found that geographical location and gender had an influence on the serum level of Zn in OP and healthy controls, but not on the serum level of Cu or Fe. No evidence of publication bias was observed. In conclusion, this meta-analysis suggests that low serum levels of Zn, Cu, and Fe seem to be important risk factors for OP and well-designed studies with adequate control for confounding factors are required in future investigations.
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Zofkova I, Nemcikova P, Matucha P (2013) Trace elements and bone health. Clin Chem Lab Med 51:1555–1561
Zheng J, Mao X, Ling J, He Q, Quan J et al (2014) Association between serum level of magnesium and postmenopausal osteoporosis: a meta-analysis. Biol Trace Elem Res. doi:10.1007/s12011-014-9961-3
Wynchank S, Saltman PD (1997) Trace elements and osteoporosis. S Afr Med J 87:473–474
Davey DA (1997) Trace elements and osteoporosis. S Afr Med J 87:902
Hsieh HS, Navia JM (1980) Zinc deficiency and bone formation in guinea pig alveolar implants. J Nutr 110:1581–1588
Burch RE, Hahn HK, Sullivan JF (1975) Newer aspects of the roles of zinc, manganese, and copper in human nutrition. Clin Chem 21:501–520
Nagata M, Kayanoma M, Takahashi T, Kaneko T, Hara H (2011) Marginal zinc deficiency in pregnant rats impairs bone matrix formation and bone mineralization in their neonates. Biol Trace Elem Res 142:190–199
Yamaguchi M, Goto M, Uchiyama S, Nakagawa T (2008) Effect of zinc on gene expression in osteoblastic MC3T3-E1 cells: enhancement of Runx2, OPG, and regucalcin mRNA expressions. Mol Cell Biochem 312:157–166
Hie M, Iitsuka N, Otsuka T, Nakanishi A, Tsukamoto I (2011) Zinc deficiency decreases osteoblasts and osteoclasts associated with the reduced expression of Runx2 and RANK. Bone 49:1152–1159
Yamaguchi M, Segawa Y, Shimokawa N, Tsuzuike N, Tagashira E (1992) Inhibitory effect of beta-alanyl-L-histidinato zinc on bone resorption in tissue culture. Pharmacology 45:292–300
Shaw JC (1988) Copper deficiency and non-accidental injury. Arch Dis Child 63:448–455
Rucker RB, Murray J, Riggins RS (1977) Nutritional copper deficiency and penicillamine administration: some effects on bone collagen and arterial elastin crosslinking. Adv Exp Med Biol 86B:619–648
Tranquilli AL, Lucino E, Garzetti GG, Romanini C (1994) Calcium, phosphorus and magnesium intakes correlate with bone mineral content in postmenopausal women. Gynecol Endocrinol 8:55–58
Katsumata S, Tsuboi R, Uehara M, Suzuki K (2006) Dietary iron deficiency decreases serum osteocalcin concentration and bone mineral density in rats. Biosci Biotechnol Biochem 70:2547–2550
Leek JC, Vogler JB, Gershwin ME, Golub MS, Hurley LS et al (1984) Studies of marginal zinc deprivation in rhesus monkeys. V. Fetal and infant skeletal effects. Am J Clin Nutr 40:1203–1212
Da CFR, Marquiegui IM, Elizaga IV (1989) Teratogenicity of zinc deficiency in the rat: study of the fetal skeleton. Teratology 39:181–194
Oner G, Bhaumick B, Bala RM (1984) Effect of zinc deficiency on serum somatomedin levels and skeletal growth in young rats. Endocrinology 114:1860–1863
Medeiros DM, Plattner A, Jennings D, Stoecker B (2002) Bone morphology, strength and density are compromised in iron-deficient rats and exacerbated by calcium restriction. J Nutr 132:3135–3141
Parelman M, Stoecker B, Baker A, Medeiros D (2006) Iron restriction negatively affects bone in female rats and mineralization of hFOB osteoblast cells. Exp Biol Med (Maywood) 231:378–386
Rico H, Roca-Botran C, Hernandez ER, Seco C, Paez E et al (2000) The effect of supplemental copper on osteopenia induced by ovariectomy in rats. Menopause 7:413–416
Rico H, Gomez-Raso N, Revilla M, Hernandez ER, Seco C et al (2000) Effects on bone loss of manganese alone or with copper supplement in ovariectomized rats. A morphometric and densitomeric study. Eur J Obstet Gynecol Reprod Biol 90:97–101
Ronaghy HA, Reinhold JG, Mahloudji M, Ghavami P, Fox MR et al (1974) Zinc supplementation of malnourished schoolboys in Iran: increased growth and other effects. Am J Clin Nutr 27:112–121
Gur A, Colpan L, Nas K, Cevik R, Sarac J et al (2002) The role of trace minerals in the pathogenesis of postmenopausal osteoporosis and a new effect of calcitonin. J Bone Miner Metab 20:39–43
Mutlu M, Argun M, Kilic E, Saraymen R, Yazar S (2007) Magnesium, zinc and copper status in osteoporotic, osteopenic and normal post-menopausal women. J Int Med Res 35:692–695
Hyun TH, Barrett-Connor E, Milne DB (2004) Zinc intakes and plasma concentrations in men with osteoporosis: the Rancho Bernardo Study. Am J Clin Nutr 80:715–721
Strause L, Saltman P, Smith KT, Bracker M, Andon MB (1994) Spinal bone loss in postmenopausal women supplemented with calcium and trace minerals. J Nutr 124:1060–1064
D’Amelio P, Cristofaro MA, Tamone C, Morra E, Di Bella S et al (2008) Role of iron metabolism and oxidative damage in postmenopausal bone loss. Bone 43:1010–1015
Marquardt ML, Done SL, Sandrock M, Berdon WE, Feldman KW (2012) Copper deficiency presenting as metabolic bone disease in extremely low birth weight, short-gut infants. Pediatrics 130:e695–e698
Relea P, Revilla M, Ripoll E, Arribas I, Villa LF et al (1995) Zinc, biochemical markers of nutrition, and type I osteoporosis. Age Ageing 24:303–307
Liu SZ, Yan H, Xu P, Li JP, Zhuang GH et al (2009) Correlation analysis between bone mineral density and serum element contents of postmenopausal women in Xi’an urban area. Biol Trace Elem Res 131:205–214
Arikan DC, Coskun A, Ozer A, Kilinc M, Atalay F et al (2011) Plasma selenium, zinc, copper and lipid levels in postmenopausal Turkish women and their relation with osteoporosis. Biol Trace Elem Res 144:407–417
Okyay E, Ertugrul C, Acar B, Sisman AR, Onvural B et al (2013) Comparative evaluation of serum levels of main minerals and postmenopausal osteoporosis. Maturitas 76:320–325
Yamaguchi M, Ozaki K (1990) Aging affects cellular zinc and protein synthesis in the femoral diaphysis of rats. Res Exp Med (Berl) 190:295–300
Segawa Y, Tsuzuike N, Tagashira E, Yamaguchi M (1993) Preventive effect of beta-alanyl-L-histidinato zinc on the deterioration of bone metabolism in ovariectomized rats. Biol Pharm Bull 16:486–489
Yamaguchi M, Uchiyama S (2003) Preventive effect of zinc acexamate administration in streptozotocin-diabetic rats: restoration of bone loss. Int J Mol Med 12:755–761
Hashizume M, Yamaguchi M (1993) Stimulatory effect of beta-alanyl-L-histidinato zinc on cell proliferation is dependent on protein synthesis in osteoblastic MC3T3-E1 cells. Mol Cell Biochem 122:59–64
Hashizume M, Yamaguchi M (1994) Effect of beta-alanyl-L-histidinato zinc on differentiation of osteoblastic MC3T3-E1 cells: increases in alkaline phosphatase activity and protein concentration. Mol Cell Biochem 131:19–24
Yamaguchi M, Kishi S (1996) Zinc compounds inhibit osteoclast-like cell formation at the earlier stage of rat marrow culture but not osteoclast function. Mol Cell Biochem 158:171–177
Yamaguchi M, Uchiyama S (2004) Receptor activator of NF-kappaB ligand-stimulated osteoclastogenesis in mouse marrow culture is suppressed by zinc in vitro. Int J Mol Med 14:81–85
Zou W, Hakim I, Tschoep K, Endres S, Bar-Shavit Z (2001) Tumor necrosis factor-alpha mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism. J Cell Biochem 83:70–83
Yamaguchi M, Inamoto K (1986) Differential effects of calcium-regulating hormones on bone metabolism in weanling rats orally administered zinc sulfate. Metabolism 35:1044–1047
Yamaguchi M, Yamaguchi R (1986) Action of zinc on bone metabolism in rats. Increases in alkaline phosphatase activity and DNA content. Biochem Pharmacol 35:773–777
Yamaguchi M, Kitajima T (1991) Effect of estrogen on bone metabolism in tissue culture: enhancement of the steroid effect by zinc. Res Exp Med (Berl) 191:145–154
Dahl SL, Rucker RB, Niklason LE (2005) Effects of copper and cross-linking on the extracellular matrix of tissue-engineered arteries. Cell Transplant 14:367–374
Rucker RB, Kosonen T, Clegg MS, Mitchell AE, Rucker BR et al (1998) Copper, lysyl oxidase, and extracellular matrix protein cross-linking. Am J Clin Nutr 67:996S–1002S
Milkovic L, Hoppe A, Detsch R, Boccaccini AR, Zarkovic N (2013) Effects of Cu-doped 45S5 bioactive glass on the lipid peroxidation-associated growth of human osteoblast-like cells in vitro. J Biomed Mater Res A. doi:10.1002/jbm.a.35032
Ding H, Gao YS, Wang Y, Hu C, Sun Y, et al. (2014) Dimethyloxaloylglycine increases the bone healing capacity of adipose-derived stem cells by promoting osteogenic differentiation and angiogenic potential. DOI: 10.1089/scd.2013.0486.
Sato K, Nohtomi K, Demura H, Takeuchi A, Kobayashi T et al (1997) Saccharated ferric oxide (SFO)-induced osteomalacia: in vitro inhibition by SFO of bone formation and 1,25-dihydroxy-vitamin D production in renal tubules. Bone 21:57–64
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The project was supported by the Guangzhou Municipal Science and Technology Project (11C32060748) and the National Natural Science Foundation of China (81100728).
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Zheng, J., Mao, X., Ling, J. et al. Low Serum Levels of Zinc, Copper, and Iron as Risk Factors for Osteoporosis: a Meta-analysis. Biol Trace Elem Res 160, 15–23 (2014). https://doi.org/10.1007/s12011-014-0031-7
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DOI: https://doi.org/10.1007/s12011-014-0031-7