The in vitro and in vivo effects of nicotine on bone, bone cells and fracture repair

Expert Opinion on Drug Safety

Volumn 12, Issue 2, 2013, Pages 209-233

  Kallala, Rami ^a   Barrow, Jonathan ^a   Graham, Simon Matthew ^b   Kanakaris, Nikolaos ^a   Giannoudis, Peter V ^a  

^a UNIVERSITY OF LEEDS   (United Kingdom)

^b ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST   (United Kingdom)

Author keywords

Bone; Chondrocytes; Fracture healing; Nicotine; Osteoblasts; Osteoclasts

Indexed keywords

BONE MORPHOGENETIC PROTEIN 2; BONE SIALOPROTEIN; CIGARETTE SMOKE; INTERLEUKIN 1; INTERLEUKIN 8; MATRIX METALLOPROTEINASE; MECAMYLAMINE; NICOTINE; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPONTIN; PARATHYROID HORMONE; PLATELET DERIVED GROWTH FACTOR AA; PROTEIN C FOS; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; TISSUE INHIBITOR OF METALLOPROTEINASE; TISSUE PLASMINOGEN ACTIVATOR; TRANSFORMING GROWTH FACTOR BETA1; TUBOCURARINE CHLORIDE; VASCULOTROPIN;

BONE; BONE CELL; BONE DEVELOPMENT; BONE MARROW CELL; BONE REGENERATION; BONE REMODELING; CARTILAGE CELL; CELL DIFFERENTIATION; CELL FUNCTION; CELL METABOLISM; CELL PROLIFERATION; DRUG BLOOD LEVEL; DRUG MEGADOSE; FRACTURE HEALING; GENE EXPRESSION; HOMEOSTASIS; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LOW DRUG DOSE; MESENCHYME CELL; NONHUMAN; OSSIFICATION; OSTEOBLAST; OSTEOCLAST; PROTEIN EXPRESSION; REVIEW; SKELETON; SMOKING CESSATION; STEADY STATE;

ANIMALS; BONE AND BONES; BONE REGENERATION; EXTRACELLULAR MATRIX PROTEINS; FRACTURES, BONE; HUMANS; NICOTINE; OSTEOBLASTS; SMOKING;

EID: 84874184718     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1517/14740338.2013.770471     Document Type: Review

References (116)

1. Centre. NI. Statistics on Smoking: England, 2010. National Statistics, United Kingdom; 2010. Report N.o.
2. Zarocostas J. WHO report warns deaths from tobacco could rise beyond eight million a year by 2030. BMJ 2008;336(7639):299
3. McBride PE. The health consequences of smoking. cardiovascular diseases. Med Clin North Am 1992;76(2):333-53
4. Newcomb P A, Carbone PP. The health consequences of smoking. Cancer. Med Clin North Am 1992;76(2):305-31
5. Sherman CB. The health consequences of cigarette smoking. Pulmonary diseases. Med Clin North Am 1992;76(2):355-75
6. Holmberg T, Bech M, Curtis T, et al. Association between passive smoking in adulthood and phalangeal bone mineral density: Results from the KRAM study-The Danish Health Examination Survey 2007-2008. Osteoporos Int 2011;22(12):2989-99
7. Tamaki J, Iki M, Fujita Y, et al. Impact of smoking on bone mineral density and bone metabolism in elderly men: The Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study. Osteoporos Int 2011;22(1):133-41
8. Law M R, Hackshaw AK. A meta-Analysis of cigarette smoking, bone mineral density and risk of hip fracture: Recognition of a major effect. BMJ 1997;315(7112):841-6 (Pubitemid 27420442)
9. Mosely L H, Finseth F. Cigarette smoking: Impairment of digital blood flow and wound healing in the hand. Hand 1977;9(2):97-101 (Pubitemid 8162550)
10. Sloan A, Hussain I, Maqsood M, et al. The effects of smoking on fracture healing. Surgeon 2010;8(2):111-16
11. Haverstock B D, Mandracchia VJ. Cigarette smoking and bone healing: Implications in foot and ankle surgery. J Foot Ankle Surg 1998;37(1):69-74; discussion 8 (Pubitemid 28051684)
12. Chen F, Osterman A L, Mahony K. Smoking and bony union after ulnashortening osteotomy. Am J Orthop 2001;30(6):486-9
13. Rajan R A, Ong M, Jones S, Fernandes J. Does smoking affect the quality of bone regenerate in paediatric limb reconstructive surgery?. J Child Orthop 2007;1(6):365-7
14. Adams C I, Keating J F, Court-Brown CM. Cigarette smoking and open tibial fractures. Injury 2001;32(1):61-5 (Pubitemid 32054725)
15. Brown C W, Orme T J, Richardson HD. The rate of pseudarthrosis (surgical nonunion) in patients who are smokers and patients who are nonsmokers: B comparison study. Spine 1986;11(9):942-3 (Pubitemid 17012173)
16. Meldrum R D, Wurtz L D, Feinberg JR, Capello WN. Does smoking affect implant survivorship in total hip arthroplasty? A preliminary retrospective case series. Iowa Orthop J 2005;25:17-24
17. Andersen T, Christensen F B, Laursen M, et al. Smoking as a predictor of negative outcome in lumbar spinal fusion. Spine 2001;26(23):2623-8 (Pubitemid 33134312)
18. Ishikawa S N, Murphy G A, Richardson EG. The effect of cigarette smoking on hindfoot fusions. Foot Ankle Int 2002;23(11):996-8 (Pubitemid 35334721)
19. Hadley M N, Reddy SV. Smoking and the human vertebral column: B review of the impact of cigarette use on vertebral bone metabolism and spinal fusion. Neurosurgery 1997;41(1):116-24
20. Holm S, Nachemson A. Nutrition of the intervertebral disc: Bcute effects of cigarette smoking. An experimental animal study. Ups J Med Sci 1988;93(1):91-9
21. Ueng S W, Lin S S, Wang C R, et al. Bone healing of tibial lengthening is delayed by cigarette smoking: Study of bone mineral density and torsional strength on rabbits. J Trauma 1999;46(1):110-15 (Pubitemid 29052984)
22. Hapidin H, Othman F, Soelaiman IN, et al. Effects of nicotine administration and nicotine cessation on bone histomorphometry and bone biomarkers in Sprague-Dawley male rats. Calcif Tissue Int 2011;88(1):41-7
23. Raikin S M, Landsman J C, Alexander VA, et al. Effect of nicotine on the rate and strength of long bone fracture healing. Clin Orthop Relat Res. 1998 (353):231-7 (Pubitemid 28385466)
24. Little C P, Burston B J, Hopkinson-Woolley J, Burge P. Failure of surgery for scaphoid non-union is associated with smoking. J Hand Surg 2006;31(3):252-5
25. Al-Hadithy N, Sewell M D, Bhavikatti M, Gikas PD. The effect of smoking on fracture healing and on various orthopaedic procedures. Acta Orthop Belg 2012;78(3):285-90
26. Roberts C S, Falls TD. Talking turkey: Fracture care and smoking cessation. Injury 2012;43(3):257-8
27. Schindeler A, McDonald M M, Bokko P, Little DG. Bone remodeling during fracture repair: The cellular picture. Semin Cell Dev Biol 2008;19(5):459-66
28. Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. 1998 (355 Suppl):S7-21
29. Barnes G L, Kostenuik P J, Gerstenfeld LC, Einhorn TA. Growth Factor Regulation of Fracture Repair. J Bone Miner Res 1999;14(11):1805-15 (Pubitemid 29521774)
30. Ogata Y. Bone sialoprotein and its transcriptional regulatory mechanism. J Periodontal Res 2008;43(2):127-35
31. Daci E, Everts V, Torrekens S, et al. Increased bone formation in mice lacking plasminogen activators. J Bone Miner Res 2003;18(7):1167-76 (Pubitemid 37294909)
32. Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of molecular aspects of bone healing. Injury 2005;36(12):1392-404 (Pubitemid 41618169)
33. Giannoudis P V, Einhorn T A, Marsh D. Fracture healing: The diamond concept. Injury 2007;38(SUPPL4):S3-6 (Pubitemid 351162866)
34. Varghese S. Matrix metalloproteinases and their inhibitors in bone: Bn overview of regulation and functions. Front Biosci 2006;11:2949-66 (Pubitemid 43800388)
35. Deckers MML, van Bezooijen R L, van der Horst G, et al. Bone Morphogenetic Proteins Stimulate Angiogenesis through Osteoblast-Derived Vascular Endothelial Growth Factor A. Endocrinology 2002;143(4):1545-53 (Pubitemid 34274386)
36. Devescovi V, Leonardi E, Ciapetti G, Cenni E. Growth factors in bone repair. Chir Organi Mov 2008;92(3):161-8
37. Rothem D E, Rothem L, Soudry M, et al. Nicotine modulates bone metabolism-Associated gene expression in osteoblast cells. J Bone Miner Metab 2009;27(5):555-61
38. Talhout R, Schulz T, Florek E, et al. Hazardous compounds in tobacco smoke. Int J Environ Res Public Health 2011;8(2):613-28
39. Patterson F, Benowitz N, Shields P, et al. Individual differences in nicotine intake per cigarette. Cancer Epidemiol Biomarkers Prev 2003;12(5):468-71 (Pubitemid 36578488)
40. Russell M A, Feyerabend C, Cole PV. Plasma nicotine levels after cigarette smoking and chewing nicotine gum. BMJ 1976;1(6017):1043-6
41. Holm H, Jarvis M J, Russell MA, Feyerabend C. Nicotine intake and dependence in Swedish snuff takers. Psychopharmacology 1992;108(4):507-11
42. Henningfield J E, Stapleton J M, Benowitz NL, et al. Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug Alcohol Depend 1993;33(1):23-9 (Pubitemid 23219906)
43. Benowitz NL. Nicotine and smokeless tobacco. CA Cancer J Clin 1988;38(4):244-7
44. Liberati A, Altman D G, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-Analyses of studies that evaluate health care interventions: Explanation and elaboration. J Clin Epidemiol 2009;62(10):e1-34
45. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-Analyses: The PRISMA statement. J Clin Epidemiol 2009;62(10):1006-12
46. Saldanha J B, Pimentel S P, Casati MZ, et al. Histologic evaluation of the effect of nicotine administration on bone regeneration. A study in dogs. Braz Oral Res 2004;18(4):345-9
47. Hastrup S G, Chen X, Bechtold J E, et al. Effect of nicotine and tobacco administration method on the mechanical properties of healing bone following closed fracture. J Orthop Res 2010;28(9):1235-9
48. Saldanha J B, Pimentel S P, Casati MZ, et al. Guided bone regeneration may be negatively influenced by nicotine administration: B histologic study in dogs. J Periodontol 2004;75(4):565-71 (Pubitemid 38635026)
49. Rothem D E, Rothem L, Dahan A, et al. Nicotinic modulation of gene expression in osteoblast cells, MG-63. Bone 2011;48(4):903-9
50. Katono T, Kawato T, Tanabe N, et al. Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells. Acta Biochim Biophys Sin (Shanghai) 2006;38(12):874-82 (Pubitemid 44952890)
51. Ho Y C, Yang S F, Huang F M, Chang YC. Up-regulation of osteolytic mediators in human osteosarcoma cells stimulated with nicotine. J Periodontal Res 2009;44(6):760-6
52. Kamer A R, El-Ghorab N, Marzec N, et al. Nicotine induced proliferation and cytokine release in osteoblastic cells. Int J Mol Med 2006;17(1):121-7
53. Pereira M L, Carvalho J C, Peres F, Fernandes MH. Effect of nicotine in matrix mineralization by human bone marrow and Saos-2 cells cultured on the surface of plasma-sprayed titanium implants. J Biomed Mater Res A. 2009; 88(1):84-93
54. Pereira M L, Carvalho J C, Peres F, et al. Behaviour of human osteoblastic cells cultured on plasma-sprayed titanium implants in the presence of nicotine. Clin Oral Implants Res 2008;19(6):582-9
55. Walker L M, Preston M R, Magnay JL, et al. Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. Bone 2001;28(6):603-8 (Pubitemid 32586069)
56. Kim B S, Kim S J, Kim H J, et al. Effects of nicotine on proliferation and osteoblast differentiation in human alveolar bone marrow-derived mesenchymal stem cells. Life Sci 2012;90(3-4):109-15
57. Ying X, Zhang W, Cheng S, et al. Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro. Knee Surg Sports Traumatol Arthrosc 2012;20(11):2329-36
58. Ying X, Cheng S, Shen Y, et al. Nicotine promotes proliferation and collagen synthesis of chondrocytes isolated from normal human and osteoarthritis patients. Mol Cell Biochem 2012;359(1-2):263-9
59. Tanaka H, Tanabe N, Shoji M, et al. Nicotine and lipopolysaccharide stimulate the formation of osteoclast-like cells by increasing macrophage colony-stimulating factor and prostaglandin E2 production by osteoblasts. Life Sci 2006;78(15):1733-40 (Pubitemid 43276481)
60. Tanaka H, Tanabe N, Suzuki N, et al. Nicotine affects mineralized nodule formation by the human osteosarcoma cell line Saos-2. Life Sci 2005;77(18):2273-84 (Pubitemid 41169962)
61. Kawakita A, Sato K, Makino H, et al. Nicotine acts on growth plate chondrocytes to delay skeletal growth through the alpha7 neuronal nicotinic acetylcholine receptor. PLoS One 2008;3(12):e3945
62. Katono T, Kawato T, Tanabe N, et al. Effects of nicotine and lipopolysaccharide on the expression of matrix metalloproteinases, plasminogen activators, and their inhibitors in human osteoblasts. Arch Oral Biol 2009;54(2):146-55
63. Ma L, Zwahlen R A, Zheng L W, Sham MH. Influence of nicotine on the biological activity of rabbit osteoblasts. Clin Oral Implants Res 2011;22(3):338-42
64. Yuhara S, Kasagi S, Inoue A, et al. Effects of nicotine on cultured cells suggest that it can influence the formation and resorption of bone. Eur J Pharmacol 1999;383(3):387-93
65. Fang M A, Frost P J, Iida-Klein A, Hahn TJ. Effects of nicotine on cellular function in UMR 106-01 osteoblast-like cells. Bone 1991;12(4):283-6
66. Ramp W K, Lenz L G, Galvin RJ. Nicotine inhibits collagen synthesis and alkaline phosphatase activity, but stimulates DNA synthesis in osteoblastlike cells. Exp Bio Med 1991;197(1):36-43
67. Galvin R J, Ramp W K, Lenz LG. Smokeless tobacco contains a nonnicotine inhibitor of bone metabolism. Toxicol Appl Pharmacol 1988;Sep 15;95(2):292-300
68. Nakayama Y, Mezawa M, Araki S, et al. Nicotine suppresses bone sialoprotein gene expression. J Periodontal Res 2009;44(5):657-63
69. Gullihorn L, Karpman R, Lippiello L. Differential effects of nicotine and smoke condensate on bone cell metabolic activity. J Orthop Trauma 2005;19(1):17-22 (Pubitemid 40309433)
70. Ying X Z, Peng L. Cheng S W, et al. [Effects of nicotine on bone marrow stromal cells proliferation and differentiation of chondrocyte in vitro]. Zhongguo gu shang 2011;24(11):935-8
71. Henemyre C L, Scales D K, Hokett SD, et al. Nicotine stimulates osteoclast resorption in a porcine marrow cell model. J Periodontol 2003;74(10):1440-6 (Pubitemid 37461456)
72. Broulik P D, Jarab J. The effect of chronic nicotine administration on bone mineral content in mice. Horm Metab Res 1993;25(4):219-21 (Pubitemid 23138684)
73. Broulik P D, Rosenkrancova J, Ruzicka P, et al. The effect of chronic nicotine administration on bone mineral content and bone strength in normal and castrated male rats. Horm Metab Res 2007;39(1):20-4 (Pubitemid 46535152)
74. Machado G J, Dias S M, Bosco A F, et al. Action of nicotine and ovariectomy on bone regeneration after tooth extraction in rats. J Oral Maxillofac Surg 2010;68(11):2675-81
75. Hapidin H, Othman F, Soelaiman IN, et al. Negative effects of nicotine on bone-resorbing cytokines and bone histomorphometric parameters in male rats. J Bone Miner Metab 2007;25(2):93-8 (Pubitemid 46328664)
76. Saito Y, Sato S, Oginuma T, et al. Effects of nicotine on guided bone augmentation in rat calvarium. Clin Oral Implants Res. 2012;[PubMed PMID: 22276738. Epub 2012/01/27. Eng
77. Hollinger J O, Schmitt J M, Hwang K, et al. Impact of nicotine on bone healing. J Biomed Mater Res 1999;45(4):294-301 (Pubitemid 29196675)
78. Pinto J R, Bosco A F, Okamoto T, et al. Effects of nicotine on the healing of extraction sockets in rats. A histological study. Braz Dent J 2002;13(1):3-9
79. Yamano S, Berley J A, Kuo W P, et al. Effects of nicotine on gene expression and osseointegration in rats. Clin Oral Implants Res 2010;21(12):1353-9
80. Berley J, Yamano S, Sukotjo C. The effect of systemic nicotine on osseointegration of titanium implants in the rat femur. J Oral Implantol 2010;36(3):185-93
81. Glowacki J, Schulten A J, Perrott D, Kaban LB. Nicotine impairs distraction osteogenesis in the rat mandible. Int J Oral Maxillofac Surg 2008;37(2):156-61 (Pubitemid 351220974)
82. Cesar-Neto J B, Duarte P M, Sallum EA, et al. A comparative study on the effect of nicotine administration and cigarette smoke inhalation on bone healing around titanium implants. J Periodontol 2003;74(10):1454-9 (Pubitemid 37461458)
83. Silcox DH 3rd, Daftari T, Boden S D, et al. The effect of nicotine on spinal fusion. Spine 1995;20(14):1549-53
84. Theiss S M, Boden S D, Hair G, et al. The effect of nicotine on gene expression during spine fusion. Spine 2000;25(20):2588-94
85. Daftari T K, Whitesides TE J r, Heller JG, et al. Nicotine on the revascularization of bone graft. An experimental study in rabbits. Spine 1994;19(8):904-11 (Pubitemid 24136165)
86. Riebel G D, Boden S D, Whitesides TE, Hutton WC. The effect of nicotine on incorporation of cancellous bone graft in an animal model. Spine 1995;20(20):2198-202
87. Zheng L W, Ma L, Cheung LK. Changes in blood perfusion and bone healing induced by nicotine during distraction osteogenesis. Bone 2008;43(2):355-61
88. Ma L, Zheng L W, Cheung LK. Influence of nicotine on blood perfusion and bone healing during distraction osteogenesis. Ann R Australas Coll Dent Surg 2008;19:52-4
89. Ma L, Zheng L W, Sham M H, Cheung LK. Effect of nicotine on gene expression of angiogenic and osteogenic factors in a rabbit model of bone regeneration. J Oral Maxillofac Surg 2010;68(4):777-81
90. Ma L, Zheng L W, Sham M H, Cheung LK. Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing. J Bone Miner Res 2010;25(6):1305-13
91. Ma L, Sham M H, Zheng L W, Cheung LK. Influence of low-dose nicotine on bone healing. J Trauma 2011;70(6):E117-21
92. Wing K J, Fisher C G, O'Connell JX, Wing PC. Stopping nicotine exposure before surgery. The effect on spinal fusion in a rabbit model. Spine 2000;Jan;25(1):30-4 (Pubitemid 30035979)
93. Kucukdeveci O, Sarisozen B, Atici T, Ozcan R. The effect of nicotine on distraction osteogenesis: Bn experimental study on rabbits. J Trauma 2009;67(6):1376-83
94. Abulencia A E, Friedlaender G E, Troiano NW, et al. The influence of nicotine on fracture repair in rats. 45th Annual Meeting, Orthopaedic Research Society, 1-4 February 1999, Annaheim, California; 1999
95. Skott M, Andreassen T T, Ulrich-Vinther M, et al. Tobacco extract but not nicotine impairs the mechanical strength of fracture healing in rats. J Orthop Res 2006;24(7):1472-9 (Pubitemid 44083263)
96. Balatsouka D, Gotfredsen K, Lindh CH, Berglundh T. The impact of nicotine on osseointegration. An experimental study in the femur and tibia of rabbits. Clin Oral Implants Res 2005;16(4):389-95 (Pubitemid 43961017)
97. Balatsouka D, Gotfredsen K, Lindh CH, Berglundh T. The impact of nicotine on bone healing and osseointegration. Clin Oral Implants Res 2005;16(3):268-76
98. Balatsouka D, Gotfredsen K, Sorensen L, et al. Effect of systemic administration of nicotine on healing in osseous defects. An experimental study in rabbits. Part II. Clin Oral Implants Res 2006;17(5):488-94 (Pubitemid 44337351)
99. Gotfredsen K, Lindh C H, Berglundh T. Does longstanding nicotine exposure impair bone healing and osseointegration? An experimental study in rabbits. J Biomed Mater Res B, Appl Biomater 2009;91(2):918-23
100. Nociti FH J r, Stefani C M, Sallum EA, et al. Nicotine and bone density around titanium implants: B histometric study in rabbits. Implant Dent 2002;11(2):176-82
101. Fung Y K, Iwaniec U, Cullen D M, et al. Long-Term effects of nicotine on bone and calciotropic hormones in adult female rats. Pharmacol Toxicol 1999;85(4):181-7 (Pubitemid 29484984)
102. Bosco A F, Bonfante S, de Almeida JM, et al. A histologic and histometric assessment of the influence of nicotine on alveolar bone loss in rats. J Periodontol 2007;78(3):527-32
103. Syversen U, Nordsletten L, Falch JA, et al. Effect of lifelong nicotine inhalation on bone mass and mechanical properties in female rat femurs. Calcif Tissue Int 1999;65(3):246-9 (Pubitemid 29380348)
104. Iwaniec U T, Fung Y K, Akhter M P, et al. Effects of nicotine on bone mass, turnover, and strength in adult female rats. Calcif Tissue Int 2001;68(6):358-64 (Pubitemid 32619305)
105. Iwaniec U T, Fung Y K, Cullen DM, et al. Effects of nicotine on bone and calciotropic hormones in growing female rats. Calcif Tissue Int 2000;67(1):68-74 (Pubitemid 30460952)
106. Iwaniec U T, Haynatzki G R, Fung YK, et al. Effects of nicotine on bone and calciotropic hormones in aged ovariectomized rats. J Musculoskelet Neuronal Interact 2002;2(5):469-78 (Pubitemid 35023625)
107. Akhter M P, Iwaniec U T, Haynatzki GR, et al. Effects of nicotine on bone mass and strength in aged female rats. J Orthop Res 2003;21(1):14-19 (Pubitemid 36163322)
108. Reinholt F P, Hultenby K, Oldberg A, Heinegard D. Osteopontin-A possible anchor of osteoclasts to bone. Proc Nat Acad Sci USA 1990;87(12):4473-5
109. Ma L, Zheng L W, Cheung LK. Inhibitory effect of nicotine on bone regeneration in mandibular distraction osteogenesis. Front Biosci 2007;12:3256-62
110. Sharma G, Vijayaraghavan S. Nicotinic receptor signaling in nonexcitable cells. J Neurobiol 2002;53(4):524-34 (Pubitemid 35375583)
111. Blair J M, Zheng Y, Dunstan CR. RANK ligand. Int J Biochem Cell Biol 2007;39(6):1077-81 (Pubitemid 46819130)
112. Arai A, Mizoguchi T, Harada S, et al. Fos plays an essential role in the upregulation of RANK expression in osteoclast precursors within the bone microenvironment. J Cell Sci 2012;125(PT12):2910-17
113. Matsumoto M, Sudo T, Saito T, et al. Involvement of p38 mitogen-Activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kB ligand (RANKL). J Biol Chem 2000;275(40):31155-61
114. Zeidler R, Albermann K, Lang S. Nicotine and apoptosis. Apoptosis 2007;12(11):1927-43 (Pubitemid 47498221)
115. Zhang J, Chen F, Yun F, Chen J. Low level nicotine: B novel approach to reduce osteoporosis incidence. Med Hypotheses 2010;74(6):1067-8
116. Gracia MC. Possible influence of nicotine on osteoporosis. Med Hypotheses 2010;75(1):133-4