Abstract
Osteoporosis (OP) is considered to be a well-defined disease which results in high morbidity and mortality. In patients diagnosed with OP, low bone mass and fragile bone strength have been demonstrated to significantly increase risk of fragility fractures. To date, various anabolic and antiresorptive therapies have been applied to maintain healthy bone mass and strength. Pulsed electromagnetic fields (PEMFs) are employed to treat patients suffering from delayed fracture healing and nonunions. Although PEMFs stimulate osteoblastogenesis, suppress osteoclastogenesis, and influence the activity of bone marrow mesenchymal stem cells (BMSCs) and osteocytes, ultimately leading to retention of bone mass and strength. However, whether PEMFs could be taken into clinical use to treat OP is still unknown. Furthermore, the deeper signaling pathways underlying the way in which PEMFs influence OP remain unclear.
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Abbreviations
- ALP :
-
alkaline phosphatase
- BMD :
-
bone mineral density
- BMP-2 :
-
bone morphogenetic protein 2
- BMSCs :
-
bone marrow mesenchymal stem cells
- BSAP :
-
bone-specific alkaline phosphatase
- CA II :
-
carbonic anhydrase II
- CTSK :
-
cathepsin K
- CTX :
-
C-terminal telopeptide
- DKK1 :
-
dickkopf-related protein 1
- ECM :
-
extracellular matrix
- ERK :
-
extracellular regulated protein kinases
- GCs :
-
glucocorticoids
- GJIC :
-
gap junction intercellular communication
- HMGB1 :
-
high-mobility group protein B1
- IGF :
-
insulin-like growth factor
- IL-1β :
-
interleukin 1 beta
- IL-6 :
-
interleukin 6
- IRS-I :
-
insulin receptor substrate-I
- MMP :
-
matrix metalloproteinase
- mMSCs :
-
mesenchymal marrow stromal/stem cells
- mTOR :
-
mammalian target of rapamycin
- NFATC1 :
-
nuclear factor of activated T cells 1
- NF-κB :
-
nuclear factor kappa B
- NO :
-
nitric oxide
- NOS :
-
NO synthase
- OC :
-
osteocalcin
- OP :
-
osteoporosis
- OPG :
-
osteoprotegerin
- OVX :
-
ovariectomized
- PEMF :
-
pulsed electromagnetic fields
- PGE2 :
-
prostaglandin E2
- PINP :
-
propeptide type I collagen
- PMOP :
-
postmenopausal osteoporosis
- PPAR-γ :
-
peroxisome proliferator-activated receptor gamma
- PTH :
-
parathyroid hormone
- RANK :
-
receptor-activator of nuclear factor kappa B
- RANKL :
-
RANK ligand
- Runx2 :
-
runt-related transcription factor 2
- SCI :
-
spinal cord injury
- TGF-β :
-
transforming growth factor
- TNF-α :
-
tumor necrosis factor-alpha
- TRAcP5b :
-
tartrate-resistant acid phosphatase 5b
- VEGF :
-
vascular endothelial growth factor
References
(2001) NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, March 7-29, 2000: highlights of the conference. South Med J 94(6):569–73
Tanaka Y, Ohira T (2018) Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system. Curr Opin Pharmacol 40:110–119
Minisola S, Scillitani A, Romagnoli E (2006) Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med 355(20):2156–2157 author reply 7
Jacobs JW, de Nijs RN, Lems WF (2007) Prevention of glucocorticoid induced osteoporosis with alendronate or alfacalcidol: relations of change in bone mineral density, bone markers, and calcium homeostasis. J Rheumatol 34(5):1051–1057
Canalis E, Mazziotti G, Giustina A (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18(10):1319–1328
Liu H, Zhou J, Gu L (2017) The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy. Oncotarget 8(1):1110–1116
Liu HF, Yang L, He HC (2013) Pulsed electromagnetic fields on postmenopausal osteoporosis in Southwest China: a randomized, active-controlled clinical trial. Bioelectromagnetics 34(4):323–332
Akhter MP, Wells DJ, Short SJ (2004) Bone biomechanical properties in LRP5 mutant mice. Bone 35(1):162–169
Garland DE, Adkins RH, Matsuno NN (1999) The effect of pulsed electromagnetic fields on osteoporosis at the knee in individuals with spinal cord injury. J Spinal Cord Med 22(4):239–245
Liu HF, He HC, Yang L (2015) Pulsed electromagnetic fields for postmenopausal osteoporosis and concomitant lumbar osteoarthritis in southwest China using proximal femur bone mineral density as the primary endpoint: study protocol for a randomized controlled trial. Trials 16:265
Wang T, He C, Yu X (2017) Pro-inflammatory cytokines: new potential therapeutic targets for obesity-related bone disorders. Curr Drug Targets 18(14):1664–1675
Sun LY, Hsieh DK, Yu TC (2009) Effect of pulsed electromagnetic field on the proliferation and differentiation potential of human bone marrow mesenchymal stem cells. Bioelectromagnetics 30(4):251–260
Jansen JH, van der Jagt OP, Punt BJ et al (2010) Stimulation of osteogenic differentiation in human osteoprogenitor cells by pulsed electromagnetic fields: an in vitro study. BMC Musculoskelet Disord 11:188
Spiegelman BM, Ginty CA (1983) Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 35(3 Pt 2):657–666
Rodriguez Fernandez JL, Ben-Ze'ev A (1989) Regulation of fibronectin, integrin and cytoskeleton expression in differentiating adipocytes: inhibition by extracellular matrix and polylysine. Differentiation 42(2):65–74
McBeath R, Pirone DM, Nelson CM (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6(4):483–495
Ongaro A, Pellati A, Bagheri L (2014) Pulsed electromagnetic fields stimulate osteogenic differentiation in human bone marrow and adipose tissue derived mesenchymal stem cells. Bioelectromagnetics 35(6):426–436
Lu T, Huang YX, Zhang C (2015) Effect of pulsed electromagnetic field therapy on the osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells. Genet Mol Res 14(3):11535–11542
Ongaro A, Varani K, Masieri FF (2012) Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E(2) and cytokine release in human osteoarthritic synovial fibroblasts. J Cell Physiol 227(6):2461–2469
Vincenzi F, Targa M, Corciulo C (2013) Pulsed electromagnetic fields increased the anti-inflammatory effect of A(2)A and A(3) adenosine receptors in human T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. PLoS One 8(5):e65561
Gharibi B, Abraham AA, Ham J (2011) Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. J Bone Miner Res 26(9):2112–2124
Lo KW, Kan HM, Ashe KM et al (2012) The small molecule PKA-specific cyclic AMP analogue as an inducer of osteoblast-like cells differentiation and mineralization. J Tissue Eng Regen Med 6(1):40–48
Carroll SH, Wigner NA, Kulkarni N (2012) A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J Biol Chem 287(19):15718–15727
Carroll SH, Ravid K (2013) Differentiation of mesenchymal stem cells to osteoblasts and chondrocytes: a focus on adenosine receptors. Expert Rev Mol Med 15:e1
Martin SK, Fitter S, Dutta AK (2015) Brief report: the differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem Cells 33(4):1359–1365
Sarbassov DD, Ali SM, Sengupta S (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168
Ferroni L, Gardin C, Dolkart O (2018) Pulsed electromagnetic fields increase osteogenetic commitment of MSCs via the mTOR pathway in TNF-alpha mediated inflammatory conditions: an in-vitro study. Sci Rep 8(1):5108
Diniz P, Shomura K, Soejima K (2002) Effects of pulsed electromagnetic field (PEMF) stimulation on bone tissue like formation are dependent on the maturation stages of the osteoblasts. Bioelectromagnetics 23(5):398–405
Chang WH, Chen LT, Sun JS et al (2004) Effect of pulse-burst electromagnetic field stimulation on osteoblast cell activities. Bioelectromagnetics 25(6):457–465
Li JK, Lin JC, Liu HC et al (2007) Cytokine release from osteoblasts in response to different intensities of pulsed electromagnetic field stimulation. Electromagn Biol Med 26(3):153–165
Chen J, He HC, Xia QJ (2010) Effects of pulsed electromagnetic fields on the mRNA expression of RANK and CAII in ovariectomized rat osteoclast-like cell. Connect Tissue Res 51(1):1–7
Sollazzo V, Palmieri A, Pezzetti F (2010) Effects of pulsed electromagnetic fields on human osteoblastlike cells (MG-63): a pilot study. Clin Orthop Relat Res 468(8):2260–2277
Fitzsimmons RJ, Ryaby JT, Mohan S (1995) Combined magnetic fields increase insulin-like growth factor-II in TE-85 human osteosarcoma bone cell cultures. Endocrinology 136(7):3100–3106
Lohmann CH, Schwartz Z, Liu Y (2000) Pulsed electromagnetic field stimulation of MG63 osteoblast-like cells affects differentiation and local factor production. J Orthop Res 18(4):637–646
Sun J, Liu X, Tong J et al (2014) Fluid shear stress induces calcium transients in osteoblasts through depolarization of osteoblastic membrane. J Biomech 47(16):3903–3908
Zhai M, Jing D, Tong S et al (2016) Pulsed electromagnetic fields promote in vitro osteoblastogenesis through a Wnt/beta-catenin signaling-associated mechanism. Bioelectromagnetics
Lee JH, McLeod KJ (2000) Morphologic responses of osteoblast-like cells in monolayer culture to ELF electromagnetic fields. Bioelectromagnetics 21(2):129–136
Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19(2):179–192
Zhou J, Li X, Liao Y (2015) Pulsed electromagnetic fields inhibit bone loss in streptozotocin-induced diabetic rats. Endocrine 49(1):258–266
Patterson TE, Sakai Y, Grabiner MD (2006) Exposure of murine cells to pulsed electromagnetic fields rapidly activates the mTOR signaling pathway. Bioelectromagnetics 27(7):535–544
Schwartz Z, Simon BJ, Duran MA (2008) Pulsed electromagnetic fields enhance BMP-2 dependent osteoblastic differentiation of human mesenchymal stem cells. J Orthop Res 26(9):1250–1255
Mundy GR (2006) Nutritional modulators of bone remodeling during aging. Am J Clin Nutr 83(2):427s–430s
Bessa PC, Casal M, Reis RL (2008) Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J Tissue Eng Regen Med 2(2–3):81–96
Smith TL, Wong-Gibbons D, Maultsby J (2004) Microcirculatory effects of pulsed electromagnetic fields. J Orthop Res 22(1):80–84
Mancini L, Moradi-Bidhendi N, Becherini L (2000) The biphasic effects of nitric oxide in primary rat osteoblasts are cGMP dependent. Biochem Biophys Res Commun 274(2):477–481
Chang K, Hong-Shong Chang W, Yu YH (2004) Pulsed electromagnetic field stimulation of bone marrow cells derived from ovariectomized rats affects osteoclast formation and local factor production. Bioelectromagnetics 25(2):134–141
Chang K, Chang WH, Tsai MT et al (2006) Pulsed electromagnetic fields accelerate apoptotic rate in osteoclasts. Connect Tissue Res 47(4):222–228
Chang K, Chang WH, Huang S (2005) Pulsed electromagnetic fields stimulation affects osteoclast formation by modulation of osteoprotegerin, RANK ligand and macrophage colony-stimulating factor. J Orthop Res 23(6):1308–1314
Borsje MA, Ren Y, de Haan-Visser HW et al (2010) Comparison of low-intensity pulsed ultrasound and pulsed electromagnetic field treatments on OPG and RANKL expression in human osteoblast-like cells. Angle Orthod 80(3):498–503
Lacey DL, Timms E, Tan HL (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93(2):165–176
Zhou J, Liao Y, Xie H (2017) Effects of combined treatment with ibandronate and pulsed electromagnetic field on ovariectomy-induced osteoporosis in rats. Bioelectromagnetics 38(1):31–40
Tschon M, Veronesi F, Contartese D (2018) Effects of pulsed electromagnetic fields and platelet rich plasma in preventing osteoclastogenesis in an in vitro model of osteolysis. J Cell Physiol 233(3):2645–2656
He J, Zhang Y, Chen J (2015) Effects of pulsed electromagnetic fields on the expression of NFATc1 and CAII in mouse osteoclast-like cells. Aging Clin Exp Res 27(1):13–19
Ishida N, Hayashi K, Hoshijima M (2002) Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem 277(43):41147–41156
Koga T, Matsui Y, Asagiri M (2005) NFAT and Osterix cooperatively regulate bone formation. Nat Med 11(8):880–885
Zhang J, Xu H, Han Z (2017) Pulsed electromagnetic field inhibits RANKL-dependent osteoclastic differentiation in RAW264.7 cells through the Ca(2+)-calcineurin-NFATc1 signaling pathway. Biochem Biophys Res Commun 482(2):289–295
Lohmann CH, Schwartz Z, Liu Y (2003) Pulsed electromagnetic fields affect phenotype and connexin 43 protein expression in MLO-Y4 osteocyte-like cells and ROS 17/2.8 osteoblast-like cells. J Orthop Res 21(2):326–334
Li JP, Chen S, Peng H (2014) Pulsed electromagnetic fields protect the balance between adipogenesis and osteogenesis on steroid-induced osteonecrosis of femoral head at the pre-collapse stage in rats. Bioelectromagnetics 35(3):170–180
Jiang Y, Gou H, Wang S et al (2016) Effect of pulsed electromagnetic field on bone formation and lipid metabolism of glucocorticoid-induced osteoporosis rats through canonical Wnt signaling pathway. Evid Based Complement Alternat Med 2016:4927035
Bassett CA (1989) Fundamental and practical aspects of therapeutic uses of pulsed electromagnetic fields (PEMFs). Crit Rev Biomed Eng 17(5):451–529
Juutilainen J, Lang S (1997) Genotoxic, carcinogenic and teratogenic effects of electromagnetic fields. Introduction and overview. Mutat Res 387(3):165–171
Huang LQ, He HC, He CQ (2008) Clinical update of pulsed electromagnetic fields on osteoporosis. Chin Med J 121(20):2095–2099
Roozbeh N, Abdi F (2018) Influence of radiofrequency electromagnetic fields on the fertility system: protocol for a systematic review and meta-analysis. JMIR Res Protoc 7(2):e33
Tabrah F, Hoffmeier M, Gilbert F Jr (1990) Bone density changes in osteoporosis-prone women exposed to pulsed electromagnetic fields (PEMFs). J Bone Miner Res 5(5):437–442
Tabrah FL, Ross P, Hoffmeier M (1998) Clinical report on long-term bone density after short-term EMF application. Bioelectromagnetics 19(2):75–78
Giordano N, Battisti E, Geraci S (2001) Effect of electromagnetic fields on bone mineral density and biochemical markers of bone turnover in osteoporosis: a single-blind, ramdomized pilot study. Curr Ther Res 62(3):187–193
Spadaro JA, Short WH, Sheehe PR (2011) Electromagnetic effects on forearm disuse osteopenia: a randomized, double-blind, sham-controlled study. Bioelectromagnetics 32(4):273–282
Matsunaga S, Sakou T, Ijiri K (1996) Osteogenesis by pulsing electromagnetic fields (PEMFs): optimum stimulation setting. In Vivo 10(3):351–356
Zati A, Gnudi S, Mongiorgi R (1993) Effects of pulsed magnetic fields in the therapy of osteoporosis induced by ovariectomy in the rat. Boll Soc Ital Biol Sper 69(7–8):469–475
Sert C, Mustafa D, Duz MZ et al (2002) The preventive effect on bone loss of 50-Hz, 1-mT electromagnetic field in ovariectomized rats. J Bone Miner Metab 20(6):345–349
Zhou J, Chen S, Guo H (2013) Pulsed electromagnetic field stimulates osteoprotegerin and reduces RANKL expression in ovariectomized rats. Rheumatol Int 33(5):1135–1141
Shen WW, Zhao JH (2010) Pulsed electromagnetic fields stimulation affects BMD and local factor production of rats with disuse osteoporosis. Bioelectromagnetics 31(2):113–119
Androjna C, Fort B, Zborowski M (2014) Pulsed electromagnetic field treatment enhances healing callus biomechanical properties in an animal model of osteoporotic fracture. Bioelectromagnetics 35(6):396–405
Jing D, Cai J, Wu Y (2014) Pulsed electromagnetic fields partially preserve bone mass, microarchitecture, and strength by promoting bone formation in hindlimb-suspended rats. J Bone Miner Res 29(10):2250–2261
Jing D, Cai J, Shen G (2011) The preventive effects of pulsed electromagnetic fields on diabetic bone loss in streptozotocin-treated rats. Osteoporos Int 22(6):1885–1895
Jing D, Li F, Jiang M (2013) Pulsed electromagnetic fields improve bone microstructure and strength in ovariectomized rats through a Wnt/Lrp5/beta-catenin signaling-associated mechanism. PLoS One 8(11):e79377
Jing D, Shen G, Huang J (2010) Circadian rhythm affects the preventive role of pulsed electromagnetic fields on ovariectomy-induced osteoporosis in rats. Bone 46(2):487–495
Chang K, Chang WH (2003) Pulsed electromagnetic fields prevent osteoporosis in an ovariectomized female rat model: a prostaglandin E2-associated process. Bioelectromagnetics 24(3):189–198
Wang T, Yu X, He C (2018) Pro-inflammatory cytokines: cellular and molecular drug targets for glucocorticoid-induced-osteoporosis via osteocyte. Curr Drug Targets
Gao J, Cheng TS, Qin A (2016) Glucocorticoid impairs cell-cell communication by autophagy-mediated degradation of connexin 43 in osteocytes. Oncotarget 7(19):26966–26978
Watts NB, Bilezikian JP, Camacho PM, Greenspan S, Harris S, Hodgson S, Kleerekoper M, Luckey M, McClung M, Pollack R, Petak S (2010) American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 16(Suppl 3):1–37
Lewiecki EM, Binkley N, Morgan SL (2016) Best practices for dual-energy X-ray absorptiometry measurement and reporting: International Society for Clinical Densitometry Guidance. J Clin Densitom 19(2):127–140
Lin HY, Lu KH (2010) Repairing large bone fractures with low frequency electromagnetic fields. J Orthop Res 28(2):265–270
Lin HY, Lin YJ (2011) In vitro effects of low frequency electromagnetic fields on osteoblast proliferation and maturation in an inflammatory environment. Bioelectromagnetics 32(7):552–560
Martino CF, Belchenko D, Ferguson V (2008) The effects of pulsed electromagnetic fields on the cellular activity of SaOS-2 cells. Bioelectromagnetics 29(2):125–132
Zhou J, Ming LG, Ge BF (2011) Effects of 50 Hz sinusoidal electromagnetic fields of different intensities on proliferation, differentiation and mineralization potentials of rat osteoblasts. Bone 49(4):753–761
Zhou J, Wang JQ, Ge BF (2012) Effect of 3.6-mT sinusoidal electromagnetic fields on proliferation and differentiation of osteoblasts in vitro. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 34(4):353–358
Cheng G, Zhai Y, Chen K (2011) Sinusoidal electromagnetic field stimulates rat osteoblast differentiation and maturation via activation of NO-cGMP-PKG pathway. Nitric Oxide 25(3):316–325
Yan JL, Zhou J, Ma HP (2015) Pulsed electromagnetic fields promote osteoblast mineralization and maturation needing the existence of primary cilia. Mol Cell Endocrinol 404:132–140
Chang K, Chang WH, Wu ML et al (2003) Effects of different intensities of extremely low frequency pulsed electromagnetic fields on formation of osteoclast-like cells. Bioelectromagnetics 24(6):431–439
Catalano A, Loddo S, Bellone F (2018) Pulsed electromagnetic fields modulate bone metabolism via RANKL/OPG and Wnt/beta-catenin pathways in women with postmenopausal osteoporosis: a pilot study. Bone 116:42–46
Zhu S, He H, Zhang C (2017) Effects of pulsed electromagnetic fields on postmenopausal osteoporosis. Bioelectromagnetics 38(6):406–424
Hug K, Roosli M (2012) Therapeutic effects of whole-body devices applying pulsed electromagnetic fields (PEMF): a systematic literature review. Bioelectromagnetics 33(2):95–105
Gwechenberger M, Rauscha F, Stix G (2006) Interference of programmed electromagnetic stimulation with pacemakers and automatic implantable cardioverter defibrillators. Bioelectromagnetics 27(5):365–377
Ahlbom A, Day N, Feychting M (2000) A pooled analysis of magnetic fields and childhood leukaemia. Br J Cancer 83(5):692–698
Kheifets L, Ahlbom A, Crespi CM (2010) Pooled analysis of recent studies on magnetic fields and childhood leukaemia. Br J Cancer 103(7):1128–1135
Crocetti S, Beyer C, Schade G (2013) Low intensity and frequency pulsed electromagnetic fields selectively impair breast cancer cell viability. PLoS One 8(9):e72944
Lin IL, Chou HL, Lee JC (2014) The antiproliferative effect of C2-ceramide on lung cancer cells through apoptosis by inhibiting Akt and NFkappaB. Cancer Cell Int 14(1):1
Morabito C, Guarnieri S, Fano G et al (2010) Effects of acute and chronic low frequency electromagnetic field exposure on PC12 cells during neuronal differentiation. Cell Physiol Biochem 26(6):947–958
Kleinerman RA, Linet MS, Hatch EE (2005) Self-reported electrical appliance use and risk of adult brain tumors. Am J Epidemiol 161(2):136–146
Abel EL, Hendrix SL, McNeeley GS et al (2007) Use of electric blankets and association with prevalence of endometrial cancer. Eur J Cancer Prev 16(3):243–250
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We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.
Funding
This work was supported by Grants from National Natural ScienceFoundation of China (81572236 to C Q He), the Chengdu Bureau ofScience and Technology(No. 2015-HM02-00042-SF to C Q He )andSichuan science and Technology (No2015$Z0054 to C Q He).
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Wang, T., Yang, L., Jiang, J. et al. Pulsed electromagnetic fields: promising treatment for osteoporosis. Osteoporos Int 30, 267–276 (2019). https://doi.org/10.1007/s00198-018-04822-6
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DOI: https://doi.org/10.1007/s00198-018-04822-6