Pulsed electromagnetic fields preserve bone architecture and mechanical properties and stimulate porous implant osseointegration by promoting bone anabolism in type 1 diabetic rabbits

Abstract

Summary

The effects of exogenous pulsed electromagnetic field (PEMF) stimulation on T1DM-associated osteopathy were investigated in alloxan-treated rabbits. We found that PEMF improved bone architecture, mechanical properties, and porous titanium (pTi) osseointegration by promoting bone anabolism through a canonical Wnt/β-catenin signaling-associated mechanism, and revealed the clinical potential of PEMF stimulation for the treatment of T1DM-associated bone complications.

Introduction

Type 1 diabetes mellitus (T1DM) is associated with deteriorated bone architecture and impaired osseous healing potential; nonetheless, effective methods for resisting T1DM-associated osteopenia/osteoporosis and promoting bone defect/fracture healing are still lacking. PEMF, as a safe and noninvasive method, have proven to be effective for promoting osteogenesis, whereas the potential effects of PEMF on T1DM osteopathy remain poorly understood.

Methods

We herein investigated the effects of PEMF stimulation on bone architecture, mechanical properties, bone turnover, and its potential molecular mechanisms in alloxan-treated diabetic rabbits. We also developed novel nontoxic Ti2448 pTi implants with closer elastic modulus with natural bone and investigated the impacts of PEMF on pTi osseointegration for T1DM bone-defect repair.

Results

The deteriorations of cancellous and cortical bone architecture and tissue-level mechanical strength were attenuated by 8-week PEMF stimulation. PEMF also promoted osseointegration and stimulated more adequate bone ingrowths into the pore spaces of pTi in T1DM long-bone defects. Moreover, T1DM-associated reduction of bone formation was significantly attenuated by PEMF, whereas PEMF exerted no impacts on bone resorption. We also found PEMF-induced activation of osteoblastogenesis-related Wnt/β-catenin signaling in T1DM skeletons, but PEMF did not alter osteoclastogenesis-associated RANKL/RANK signaling gene expression.

Conclusion

We reveal that PEMF improved bone architecture, mechanical properties, and pTi osseointegration by promoting bone anabolism through a canonical Wnt/β-catenin signaling-associated mechanism. This study enriches our basic knowledge for understanding skeletal sensitivity in response to external electromagnetic signals, and also opens new treatment alternatives for T1DM-associated osteopenia/osteoporosis and osseous defects in an easy and highly efficient manner.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103:137–149

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Weber DR, Schwartz G (2016) Epidemiology of skeletal health in type 1 diabetes. Curr Osteoporos Rep 14:327–336

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Danielson KK, Elliott ME, LeCaire T, Binkley N, Palta M (2009) Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes. Osteoporos Int 20:923–933

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Mastrandrea LD, Wactawski-Wende J, Donahue RP, Hovey KM, Clark A, Quattrin T (2008) Young women with type 1 diabetes have lower bone mineral density that persists over time. Diabetes Care 31:1729–1735

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Shanbhogue VV, Hansen S, Frost M, Jorgensen NR, Hermann AP, Henriksen JE, Brixen K (2015) Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in adult patients with type 1 diabetes mellitus. J Bone Miner Res 30:2188–2199

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Abdalrahaman N, McComb C, Foster JE, McLean J, Lindsay RS, McClure J, McMillan M, Drummond R, Gordon D, McKay GA, Shaikh MG, Perry CG, Ahmed SF (2015) Deficits in trabecular bone microarchitecture in young women with type 1 diabetes mellitus. J Bone Miner Res 30:1386–1393

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Forsen L, Meyer HE, Midthjell K, Edna TH (1999) Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trondelag Health Survey. Diabetologia 42:920–925

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Nicodemus KK, Folsom AR (2001) Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 24:1192–1197

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Yoshizawa T, Hinoi E, Jung DY, Kajimura D, Ferron M, Seo J, Graff JM, Kim JK, Karsenty G (2009) The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest 119:2807–2817

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Kajimura D, Myers MG Jr, Chua SC Jr, Wang Q, Kim JK, Kaestner KH, Karsenty G (2009) An osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. Ann N Y Acad Sci 1173 Suppl 1:E20–E30

    Article  PubMed  Google Scholar 

  11. 11.

    Loder RT (1988) The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res:210-216

  12. 12.

    Bibbo C, Lin SS, Beam HA, Behrens FF (2001) Complications of ankle fractures in diabetic patients. The Orthopedic clinics of North America 32:113–133

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Yee CS, Xie L, Hatsell S, Hum N, Murugesh D, Economides AN, Loots GG, Collette NM (2016) Sclerostin antibody treatment improves fracture outcomes in a type I diabetic mouse model. Bone 82:122–134

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Beam HA, Parsons JR, Lin SS (2002) The effects of blood glucose control upon fracture healing in the BB Wistar rat with diabetes mellitus. Journal of orthopaedic research: official publication of the Orthopaedic Research Society 20:1210–1216

    CAS  Article  Google Scholar 

  15. 15.

    Annibali S, Pranno N, Cristalli MP, La Monaca G, Polimeni A (2016) Survival analysis of implant in patients with diabetes mellitus: a systematic review. Implant Dent 25:663–674

    Article  PubMed  Google Scholar 

  16. 16.

    Javed F, Romanos GE (2009) Impact of diabetes mellitus and glycemic control on the osseointegration of dental implants: a systematic literature review. J Periodontol 80:1719–1730

    Article  PubMed  Google Scholar 

  17. 17.

    Iyama S, Takeshita F, Ayukawa Y, Kido MA, Suetsugu T, Tanaka T (1997) A study of the regional distribution of bone formed around hydroxyapatite implants in the tibiae of streptozotocin-induced diabetic rats using multiple fluorescent labeling and confocal laser scanning microscopy. J Periodontol 68:1169–1175

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Siqueira JT, Cavalher-Machado SC, Arana-Chavez VE, Sannomiya P (2003) Bone formation around titanium implants in the rat tibia: role of insulin. Implant Dent 12:242–251

    Article  PubMed  Google Scholar 

  19. 19.

    Bassett CA, Pawluk RJ, Pilla AA (1974) Augmentation of bone repair by inductively coupled electromagnetic fields. Science 184:575–577

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Tabrah F, Hoffmeier M, Gilbert F Jr, Batkin S, Bassett CA (1990) Bone density changes in osteoporosis-prone women exposed to pulsed electromagnetic fields (PEMFs). J Bone Miner Res 5:437–442

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Eyres KS, Saleh M, Kanis JA (1996) Effect of pulsed electromagnetic fields on bone formation and bone loss during limb lengthening. Bone 18:505–509

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Garland DE, Adkins RH, Matsuno NN, Stewart CA (1999) The effect of pulsed electromagnetic fields on osteoporosis at the knee in individuals with spinal cord injury. J Spinal Cord Med 22:239–245

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Chang K, Chang WH (2003) Pulsed electromagnetic fields prevent osteoporosis in an ovariectomized female rat model: a prostaglandin E2-associated process. Bioelectromagnetics 24:189–198

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Jing D, Cai J, Wu Y et al (2014) Pulsed electromagnetic fields partially preserve bone mass, microarchitecture, and strength by promoting bone formation in Hindlimb-suspended rats. J Bone Miner Res

  25. 25.

    Sert C, Mustafa D, Duz MZ, Aksen F, Kaya A (2002) The preventive effect on bone loss of 50-Hz, 1-mT electromagnetic field in ovariectomized rats. J Bone Miner Metab 20:345–349

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Chang K, Chang WH, Huang S, Shih C (2005) Pulsed electromagnetic fields stimulation affects osteoclast formation by modulation of osteoprotegerin, RANK ligand and macrophage colony-stimulating factor. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 23:1308–1314

    CAS  Google Scholar 

  27. 27.

    Zhai M, Jing D, Tong S, Wu Y, Wang P, Zeng Z, Shen G, Wang X, Xu Q, Luo E (2016) Pulsed electromagnetic fields promote in vitro osteoblastogenesis through a Wnt/beta-catenin signaling-associated mechanism. Bioelectromagnetics

  28. 28.

    Li K, Kaaks R, Linseisen J, Rohrmann S (2012) Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart 98:920–925

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD (2002) Postmenopausal hormone replacement therapy: scientific review. JAMA 288:872–881

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Rizzoli R, Reginster JY, Boonen S, Breart G, Diez-Perez A, Felsenberg D, Kaufman JM, Kanis JA, Cooper C (2011) Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis. Calcif Tissue Int 89:91–104

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Gomes MF, Valva VN, Vieira EM, Giannasi LC, Salgado MA, Vilela-Goulart MG (2016) Homogenous demineralized dentin matrix and platelet-rich plasma for bone tissue engineering in cranioplasty of diabetic rabbits: biochemical, radiographic, and histological analysis. Int J Oral Maxillofac Surg 45:255–266

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Hou CJ, Liu JL, Li X, Bi LJ (2012) Insulin promotes bone formation in augmented maxillary sinus in diabetic rabbits. Int J Oral Maxillofac Surg 41:400–407

    Article  PubMed  Google Scholar 

  34. 34.

    Hao YL, Li SJ, Sun SY, Zheng CY, Yang R (2007) Elastic deformation behaviour of Ti-24Nb-4Zr-7.9Sn for biomedical applications. Acta Biomater 3:277–286

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Jing D, Shen G, Huang J, Xie K, Cai J, Xu Q, Wu X, Luo E (2010) Circadian rhythm affects the preventive role of pulsed electromagnetic fields on ovariectomy-induced osteoporosis in rats. Bone 46:487–495

    Article  PubMed  Google Scholar 

  36. 36.

    Hansen PS, Clarke RJ, Buhagiar KA, Hamilton E, Garcia A, White C, Rasmussen HH (2007) Alloxan-induced diabetes reduces sarcolemmal Na+-K+ pump function in rabbit ventricular myocytes. Am J Physiol Cell Physiol 292:C1070–C1077

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Shen WW, Zhao JH (2010) Pulsed electromagnetic fields stimulation affects BMD and local factor production of rats with disuse osteoporosis. Bioelectromagnetics 31:113–119

    CAS  PubMed  Google Scholar 

  38. 38.

    Grace KL, Revell WJ, Brookes M (1998) The effects of pulsed electromagnetism on fresh fracture healing: osteochondral repair in the rat femoral groove. Orthopedics 21:297–302

    CAS  PubMed  Google Scholar 

  39. 39.

    An YH, Martin KL (2003) Handbook of histology methods for bone and cartilage. Humana Press, Totowa

    Book  Google Scholar 

  40. 40.

    Smith EJ, McEvoy A, Little DG, Baldock PA, Eisman JA, Gardiner EM (2004) Transient retention of endochondral cartilaginous matrix with bisphosphonate treatment in a long-term rabbit model of distraction osteogenesis. J Bone Miner Res 19:1698–1705

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Jing D, Tong S, Zhai M, Li X, Cai J, Wu Y, Shen G, Zhang X, Xu Q, Guo Z, Luo E (2015) Effect of low-level mechanical vibration on osteogenesis and osseointegration of porous titanium implants in the repair of long bone defects. Sci Rep 5:17134

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Oliver WC, Pharr GM (1992) An improved technique for determining hardness and elastic modulus. J Mater Res 7:1564–1583

    CAS  Article  Google Scholar 

  43. 43.

    Letic-Gavrilovic A, Scandurra R, Abe K (2000) Genetic potential of interfacial guided osteogenesis in implant devices. Dent Mater J 19:99–132

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Karageorgiou V, Kaplan D (2005) Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials 26:5474–5491

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Li X, Ma XY, Feng YF, Ma ZS, Wang J, Ma TC, Qi W, Lei W, Wang L (2015) Osseointegration of chitosan coated porous titanium alloy implant by reactive oxygen species-mediated activation of the PI3K/AKT pathway under diabetic conditions. Biomaterials 36:44–54

    Article  PubMed  Google Scholar 

  46. 46.

    Mieczkowska A, Mansur SA, Irwin N, Flatt PR, Chappard D, Mabilleau G (2015) Alteration of the bone tissue material properties in type 1 diabetes mellitus: a Fourier transform infrared microspectroscopy study. Bone 76:31–39

    Article  PubMed  Google Scholar 

  47. 47.

    Farr JN, Khosla S (2016) Determinants of bone strength and quality in diabetes mellitus in humans. Bone 82:28–34

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Kalaitzoglou E, Popescu I, Bunn RC, Fowlkes JL, Thrailkill KM (2016) Effects of type 1 diabetes on osteoblasts, osteocytes, and osteoclasts. Curr Osteoporos Rep 14:310–319

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Hie M, Shimono M, Fujii K, Tsukamoto I (2007) Increased cathepsin K and tartrate-resistant acid phosphatase expression in bone of streptozotocin-induced diabetic rats. Bone 41:1045–1050

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Hie M, Yamazaki M, Tsukamoto I (2009) Curcumin suppresses increased bone resorption by inhibiting osteoclastogenesis in rats with streptozotocin-induced diabetes. Eur J Pharmacol 621:1–9

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Jing D, Li F, Jiang M, Cai J, Wu Y, Xie K, Wu X, Tang C, Liu J, Guo W, Shen G, Luo E (2013) Pulsed electromagnetic fields improve bone microstructure and strength in ovariectomized rats through a Wnt/Lrp5/beta-catenin signaling-associated mechanism. PLoS One 8:e79377

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hofbauer LC, Schoppet M (2004) Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 292:490–495

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Grana DR, Marcos HJ, Kokubu GA (2008) Pulsed electromagnetic fields as adjuvant therapy in bone healing and peri-implant bone formation: an experimental study in rats. Acta Odontol Latinoam 21:77–83

    PubMed  Google Scholar 

  56. 56.

    Jing D, Zhai M, Tong S, Xu F, Cai J, Shen G, Wu Y, Li X, Xie K, Liu J, Xu Q, Luo E (2016) Pulsed electromagnetic fields promote osteogenesis and osseointegration of porous titanium implants in bone defect repair through a Wnt/beta-catenin signaling-associated mechanism. Sci Rep 6:32045

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Matsumoto H, Ochi M, Abiko Y, Hirose Y, Kaku T, Sakaguchi K (2000) Pulsed electromagnetic fields promote bone formation around dental implants inserted into the femur of rabbits. Clin Oral Implants Res 11:354–360

    CAS  Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Chinese National Natural Science Foundation (No. 31500760 and 81471806).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to J. Cai or D. Jing.

Ethics declarations

This study was approved by the Institutional Animal Care and Use Committee of the Fourth Military Medical University, and all animal procedures were strictly performed in accordance with the approved guidelines.

Conflicts of interest

None.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cai, J., Li, W., Sun, T. et al. Pulsed electromagnetic fields preserve bone architecture and mechanical properties and stimulate porous implant osseointegration by promoting bone anabolism in type 1 diabetic rabbits. Osteoporos Int 29, 1177–1191 (2018). https://doi.org/10.1007/s00198-018-4392-1

Download citation

Keywords

  • Bone turnover
  • Osseointegration
  • Osteopenia/osteoporosis
  • Pulsed electromagnetic fields
  • Type 1 diabetes mellitus