Abstract
Osteoporosis is a systemic disease characterized by bone degradation and decreased bone mass that promotes increased bone fragility and eventual fracture risk. Studies have investigated the use of sodium fluoride (NaF) for the treatment of osteoporosis. However, fluoride can alter glucose homeostasis. The aim of this study was to evaluate the effects of NaF intake (50 mg/L) from water on the following parameters of ovariectomized (OVX) rats: (1) tyrosine phosphorylation status of insulin receptor substrate (pp185 (IRS-1/IRS-2)) in white adipose tissue; (2) insulin sensitivity; (3) plasma concentrations of glucose, insulin, total cholesterol, triglyceride, TNF-α, IL-6, osteocalcin, calcium, and fluoride; (4) bone density and biomechanical properties in the tibia; and (5) tibia histomorphometric analysis. Fifty-two Wistar rats (2 months old) were ovariectomized and distributed into two groups: control group (OVX-C) and NaF group (OVX-F), which was subjected to treatment with NaF (50 mg/L) administered in drinking water for 42 days. The chronic treatment with NaF promoted (1) a decrease in pp185 (IRS-1/IRS-2) tyrosine phosphorylation status after insulin infusion in white adipose tissue and in insulin sensitivity; (2) an increase in the plasma concentration of insulin, fluoride, osteocalcin, calcium, triglyceride, VLDL-cholesterol, TNF-α, and IL-6; (3) a reduction in the trabecular width, bone area, stiffness, maximum strength, and tenacity; (4) no changes in body weight, food and water intake, plasma glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, bone mineral content, and bone mineral density. It was concluded that chronic treatment with NaF (50 mg/L) in OVX rats causes a decrease in insulin sensitivity, insulin signaling transduction, and biochemical, biomechanical, and histomorphometric bone parameters.
Similar content being viewed by others
References
Veldhuis-Vlug AG, Fliers E, Bisschop PH (2013) Bone as a regulator of glucose metabolism. Neth J Med 71:396–400
Bonucci E, Ballanti P (2013) Osteoporosis: bone remodeling and animal models. Toxicol Pathol 000:1–13
Schnitzler CM, Solomon L (1985) Trabecular stress-fractures during fluoride therapy for osteoporosis. Skelet Radiol 14:276–279
Grey A, Garg S, Dray M, Purvis L, Horne A, Callon K, Gamble G, Bolland M, Reid IR, Cundy T (2013) Low-dose fluoride in postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab 98:2301–2307
Carvalho CRO, Brenelli SL, Silva AC, Nunes ALB, Velloso LA, Saad MJA (1996) Effect of aging on insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of rats. Endocrinology 137:151–159
Román LDA, de la Fuente AR, de Luis J, Pérez JL, González M (2004) Papel del flúor en la osteoporosis. Endocrinologia y Nutrición 1:426–432
Jiang Y, Zhao J, Van Audekercke R, Dequeker J, Geusens P (1996) Effects of low-dose long-term sodium fluoride preventive treatment on rat bone mass and biomechanical properties. Calc Tissue Int 58:30–39
Riggs BL, Hodgson SF, Ofallon WM, Chao EYS, Wahner HW, Muhs JM, Cedel SL, Melton LJ (1990) Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 322:802–809
Trivedi N, Mithal A, Gupta SK, Godbole MM (1993) Reversible impairment of glucose-tolerance in patients with endemic fluorosis. Diabetologia 36:826–828
Grucka-Mamczar E, Birkner E, Kasperczyk S, Kasperczyk A, Chlubek D, Samujlo D, Ceglowska A (2004) Lipid balance in rats with fluoride-induced hyperglycemia. Fluoride 37:195–200
Chiba FY, Colombo NH, Shirakashi DJ, da Silva VC, Saliba Moimaz SA, Saliba Garbin CA, Antoniali C, Sumida DH (2012) NaF treatment increases TNF-alpha and resistin concentrations and reduces insulin signal in rats. J Fluoride Chem 136:3–7
Chiba FY, Colombo NH, Shirakashi DJ, de Souza Gomes WD, Saliba Moimaz SA, Saliba Garbin CA, Silva CA, Sumida DH (2010) Insulin signal decrease in muscle but not in the liver of castrated male rats from chronic exposure to fluoride. Fluoride 43:25–30
Chiba FY, Saliba Garbin CA, Sumida DH (2012) Effect of fluoride intake on carbohydrate metabolism, glucose tolerance, and insulin signaling. Fluoride 45:236–241
Farley JR, Wergedal JE, Baylink DJ (1983) Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells. Science 222:330–332
Chehoud KA, Chiba FY, Sassaki KT, Saliba Garbin CA, Sumida DH (2008) Effects of fluoride intake on insulin sensitivity and insulin signal transduction. Fluoride 41:270–275
Rigalli A, Ballina JC, Roveri E, Puche RC (1990) Inhibitory effect of fluoride on the secretion of insulin. Calc Tissue Int 46:333–338
Claro FA, Sa Lima JR, Salgado MAC, Gomes MF (2005) Porous polyethylene for tissue engineering applications in diabetic rats treated with calcitonin: histomorphometric analysis. Int J Oral Maxillofac Implants 20:211–219
Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al. (2000) Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 23:57–63
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502
Taves DR (1968) Separation of fluoride by rapid diffusion using hexamethyldisiloxane. Talanta 15:969–974
Whitford GM (1996) The metabolism and toxicity of fluoride. Karger
Buzalaf MAR, Fuhushima R, Granjeiro JM, Cury JA (2002) Correlation between plasma and nail fluoride concentrations in rats given different levels of fluoride in water. Fluoride 35:185–192
Rigalli A, Alloatti R, Puche RC (1999) Measurement of total and diffusible serum fluoride. J Clin Lab Anal 13:151–157
Shirakashi DJ, Leal RP, Colombo NH, Chiba FY, Garbin CAS, Jardim EG, Antoniali C, Sumida DH (2013) Maternal periodontal disease in rats decreases insulin sensitivity and insulin signaling in adult offspring. J Periodontol 84:407–414
Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 28:1–16
Pedrosa WF Jr, Okamoto R, Faria PE, Arnez MF, Xavier SP, Salata LA (2009) Immunohistochemical, tomographic and histological study on onlay bone graft remodeling. Part II: Calvarial Bone Clin Oral Implants Res 20:1254–1264
Kasuga M, Hedo JA, Yamada KM, Kahn CR (1982) The structure of insulin receptor and its subunits. evidence for multiple nonreduced forms and a 210,000 possible proreceptor. J Biol Chem 257:10392–10399
Chou CK, Dull TJ, Russell DS, Gherzi R, Lebwohl D, Ullrich A, Rosen OM (1987) Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin. J Biol Chem 262:1842–1847
Ebina Y, Araki E, Taira M, Shimada F, Craik CS, Siddle K, Pierce SB, Roth RA, Rutter WJ (1987) Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin- and antibody-stimulated glucose uptake and receptor kinase activity. Proc Natl Acad Sci U S A 84:704–708
Cesaretti MLR, Kohlmann OJ (2006) Modelos experimentais de resistência à insulina e obesidade: lições aprendidas. Arq Bras Endocrinol Metabol 50:190–197
Pihlajamäki J, Gylling H, Miettinen TA, Laakso M (2004) Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men. J Lipid Res 45:507–512
Graham LS, Tintut Y, Parhami F, Kitchen CM, Ivanov Y, Tetradis S, Effros RB (2010) Bone density and hyperlipidemia: the T-lymphocyte connection. J Bone Miner Res 25:2460–2469
Peraldi P, Spiegelman B (1998) TNF-alpha and insulin resistance: summary and future prospects. Mol Cell Biochem 182:169–175
Hotamisiligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance. Science 271:665–668
Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T (2000) Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191:275–285
de Benedetti F, Rucci N, del Fattore A, Peruzzi B, Paro R, Longo M, Vivarell M, Muratori F, Berni S, Ballanti P, Ferrari S, Teti A (2006) Impaired skeletal development in interleukin-6-transgenic mice—a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum 54:3551–3563
Martin LNC, Kayath MJ (1999) Abordagem clínico-laboratorial no diagnóstico diferencial de hipercalcemia. Arq Bras Endocrinol Metab 43:472–479
Duan XQ, Zhao ZT, Zhang XY, Wang Y, Wang H, Liu DW, Li GS, Jing L (2014) Fluoride affects calcium homeostasis and osteogenic transcription factor expressions through l-type calcium channels in osteoblast cell line. Biol Trace Elem Res 162:219–226
Dandona P, Coumar A, Gill DS, Bell J, Thomas M (1988) Sodium fluoride stimulates osteocalcin in normal subjects. Clin Endocrinol 29:437–441
Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, Mckee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469
Dambacher MA, Ittner J, Ruegsegger P (1986) Long-term fluoride therapy of postmenopausal osteoporosis. Bone 7:199–205
Kleerekoper M, Peterson EL, Nelson DA, Phillips E, Schork MA, Tilley BC, Parfitt AM (1991) A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis. Osteoporos Int 1:155–161
Haguenauer D, Welch V, Shea B, Tugwell P, Adachi JD, Wells G (2000) Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis. Osteoporos Int 11:727–738
Søgaard CH, Mosekilde L, Schwartz W, Leidig G, Minne HW, Ziegler R (1995) Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Bone 16:163–169
Søgaard CH, Mosekilde L, Thomsen JS, Richards A, Mcosker JE (1997) A comparison of the effects of two anabolic agents (fluoride and PTH) on ash density and bone strength assessed in an osteopenic rat model. Bone 20:439–449
Fernandes MS, Yanai MM, Martins GM, Iano FG, Leite AL, Cestari TM, Taga R, Buzalaf MAR, Oliveira RC (2014) Effects of fluoride in bone repair: an evaluation of RANKL, OPG and TRAP expression. Odontology 102:22–30
Shin D, Kim S, Kim KH, Lee K, Park SM (2014) Association between insulin resistance and bone mass in men. J Clin Endocrinol Metab 99:988–995
Acknowledgments
This work was supported by funds from the Coordination of Improvement of Higher Education Personnel (CAPES), Pro-rector for research, and graduate of UNESP– Univ Estadual Paulista, Brazil.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
de Cássia Alves Nunes, R., Chiba, F.Y., Pereira, A.G. et al. Effect of Sodium Fluoride on Bone Biomechanical and Histomorphometric Parameters and on Insulin Signaling and Insulin Sensitivity in Ovariectomized Rats. Biol Trace Elem Res 173, 144–153 (2016). https://doi.org/10.1007/s12011-016-0642-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-016-0642-2