Skip to main content

Advertisement

Log in

Effect of Sodium Fluoride on Bone Biomechanical and Histomorphometric Parameters and on Insulin Signaling and Insulin Sensitivity in Ovariectomized Rats

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Veldhuis-Vlug AG, Fliers E, Bisschop PH (2013) Bone as a regulator of glucose metabolism. Neth J Med 71:396–400

    CAS  PubMed  Google Scholar 

  2. Bonucci E, Ballanti P (2013) Osteoporosis: bone remodeling and animal models. Toxicol Pathol 000:1–13

    Google Scholar 

  3. Schnitzler CM, Solomon L (1985) Trabecular stress-fractures during fluoride therapy for osteoporosis. Skelet Radiol 14:276–279

    Article  CAS  Google Scholar 

  4. 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

    Article  CAS  PubMed  Google Scholar 

  5. 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

    CAS  PubMed  Google Scholar 

  6. 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

    Article  Google Scholar 

  7. 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

    Article  CAS  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. Trivedi N, Mithal A, Gupta SK, Godbole MM (1993) Reversible impairment of glucose-tolerance in patients with endemic fluorosis. Diabetologia 36:826–828

    Article  CAS  PubMed  Google Scholar 

  10. 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

    CAS  Google Scholar 

  11. 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

    Article  CAS  Google Scholar 

  12. 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

    CAS  Google Scholar 

  13. Chiba FY, Saliba Garbin CA, Sumida DH (2012) Effect of fluoride intake on carbohydrate metabolism, glucose tolerance, and insulin signaling. Fluoride 45:236–241

    Google Scholar 

  14. Farley JR, Wergedal JE, Baylink DJ (1983) Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells. Science 222:330–332

    Article  CAS  PubMed  Google Scholar 

  15. 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

    CAS  Google Scholar 

  16. Rigalli A, Ballina JC, Roveri E, Puche RC (1990) Inhibitory effect of fluoride on the secretion of insulin. Calc Tissue Int 46:333–338

    Article  CAS  Google Scholar 

  17. 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

    PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    CAS  PubMed  Google Scholar 

  20. Taves DR (1968) Separation of fluoride by rapid diffusion using hexamethyldisiloxane. Talanta 15:969–974

    Article  CAS  PubMed  Google Scholar 

  21. Whitford GM (1996) The metabolism and toxicity of fluoride. Karger

  22. 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

    CAS  Google Scholar 

  23. Rigalli A, Alloatti R, Puche RC (1999) Measurement of total and diffusible serum fluoride. J Clin Lab Anal 13:151–157

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  Google Scholar 

  26. 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

    PubMed  Google Scholar 

  27. 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

    CAS  PubMed  Google Scholar 

  28. 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

    CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cesaretti MLR, Kohlmann OJ (2006) Modelos experimentais de resistência à insulina e obesidade: lições aprendidas. Arq Bras Endocrinol Metabol 50:190–197

    Article  PubMed  Google Scholar 

  31. 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

    Article  PubMed  Google Scholar 

  32. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Peraldi P, Spiegelman B (1998) TNF-alpha and insulin resistance: summary and future prospects. Mol Cell Biochem 182:169–175

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  Google Scholar 

  35. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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

    Article  PubMed  Google Scholar 

  37. Martin LNC, Kayath MJ (1999) Abordagem clínico-laboratorial no diagnóstico diferencial de hipercalcemia. Arq Bras Endocrinol Metab 43:472–479

    Article  Google Scholar 

  38. 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

    Article  CAS  PubMed  Google Scholar 

  39. Dandona P, Coumar A, Gill DS, Bell J, Thomas M (1988) Sodium fluoride stimulates osteocalcin in normal subjects. Clin Endocrinol 29:437–441

    Article  CAS  Google Scholar 

  40. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dambacher MA, Ittner J, Ruegsegger P (1986) Long-term fluoride therapy of postmenopausal osteoporosis. Bone 7:199–205

    Article  CAS  PubMed  Google Scholar 

  42. 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

    Article  CAS  PubMed  Google Scholar 

  43. 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

    Article  CAS  PubMed  Google Scholar 

  44. 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

    Article  PubMed  Google Scholar 

  45. 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

    Article  PubMed  Google Scholar 

  46. 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

    Article  CAS  Google Scholar 

  47. 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

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors

Corresponding author

Correspondence to Doris Hissako Sumida.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-016-0642-2

Keywords

Navigation