EFFECT OF BONE MARROW DERIVED MESENCHYMAL STEM CELLS VS ALENDRONATE SODIUM IN TREATMENT OF INDUCED ESTROGEN DEFICIENCY OSTEOPOROSIS IN ALVEOLAR BONE OF ALBINO RATS.

  • Lecturer of oral biology, Faculty of dentistry, Ain Shams university.
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Background: Despite extensive efforts for the understanding and curative options for osteoporosis, it remains a critical public health threat. Alendronate sodium, an amino bisphosphonate, is a potent antiresorptive drug used in the treatment of osteoporosis in postmenopausal women. On the other hand, BMMSCS are considered one of the recent therapeutic modalities that promote bone regeneration by increasing the number and activity of osteoblasts. Hence, based on the role of alveolar bone in dentistry, it is important to study the effect of estrogen deficiency and its therapies on tooth-supporting alveolar bone. Aim: The aim of this study was to investigate the influence of an estrogen deficient state in rats, and its treatments namely BMMSCs and Alendronate sodium, on the structure of tooth-supporting alveolar bone. Methodology: Forty-eight female albino rats were divided equally into 4 groups: Gp 1 received only distilled water during the whole experimental duration. Gps 2, 3 and 4 underwent bilateral ovariectomy where Gp 2 received no treatment, group 3 was treated by Alendronate sodium and finally group 4 received BMMSCs injection. After 4 weeks samples from all groups were collected and evaluated using hematoxylin and eosin as well as Masson trichrome. Number of osteocytes and thickness of bone trabeculae were statistically analyzed. Results: The histological examination revealed obvious enhancement of the alveolar bone condition by both modalities of treatment however statistically insignificant outcomes were observed regarding mesenchymal stem cell treated group. Conclusion: BMMSCs injection does not significantly overcome the effect of the most widely used Alendronate Sodium in treatment of alveolar bone osteoporosis in ovariectomized rats.


  1. Rosen CJ, Bilezikian JP. Anabolic therapy for osteoporosis. J Clin Endocrinol Metab 2001; 86:957?64.
  2. Iwamoto J, Miyata A, Sato Y, Takeda T, Matsumoto H. Five-year alendronate treatment outcome in older postmenopausal Japanese women with osteoporosis or osteopenia and clinical risk factors for fractures. Ther Clin Risk Manag 2009; 5:773?9.
  3. Lerner UH. Bone remodeling in post-menopausal osteoporosis. J Dent Res 2006; 85:584?95.
  4. Kimmel DB. Mechanisms of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen containing biphosphonates. J Dent Res 2007; 86:1022?33.
  5. Flanagan AM, Chambers TJ. Inhibition of bone resorption by bisphosphonates: interactions between bisphosphonats, osteoclasts, and bone. Calcif Tissue Int 1991; 49:407?15.
  6. Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995; 10:1478?87.
  7. Russel RGG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999; 25:97?106.
  8. Zahrowski JJ. Bisphosphonate treatment: an orthodontic concern calling for a proactive approach. Am J Orthod Dentofacial Orthop 2007;131:311?20.
  9. Rinchuse DJ, Rinchuse DJ, Sosovicka MF, Robison JM, Pendleton R. Orthodontic treatment of patients using bisphosphonates: a report of 2 cases. Am J Orthod Dentofacial Orthop 2007; 131:321?6.
  10. Salazar M, Hernandes L, Ramos AL, Micheletti KR, Albino CC, Cuman RKN. Effect of teriparatide on induced teeth displacement in ovariectomized rats: a histomorphometric analysis. Am J Orthod Dentofacial Orthop 2011;139:e337?44
  11. Choi J, Baek SH, Lee J, Chang Y. Effects of clodronate on early alveolar bone remodeling and root resorption related to orthodontic forces: a histomorphometric analysis. Am J Orthod Dentofacial Orthop 2010;138. 548.e1?548.e8.
  12. Karras JC, Miller JR, Hodges JS, Beyer JP, Larson BE. Effect of alendronate on orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop 2009;136:843?7.
  13. Wright NC, Looker AC, Saag KG et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 2014;29:2520?2526.
  14. Leslie WD, Lix LM, Finlayson GS et al. Direct healthcare costs for 5 years post fracture in Canada: A long-term population based assessment. Osteoporos Int 2013; 24:1697?1705.
  15. Leslie WD, Morin SN. Osteoporosis epidemiology 2013: Implications for diagnosis, risk assessment, and treatment. Curr Opin Rheumatol 2014; 26:440?446.
  16. Harvey N, Dennison E, Cooper C. The epidemiology of osteoporotic fractures. In: Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Ames, Iowa, USA: John Wiley & Sons, 2013:348?356.
  17. Papadimitropoulos EA, Coyte PC, Josse RG et al. Current and projected rates of hip fracture in Canada. CMAJ 1997;157:1357?1363.
  18. Miller PD, Papapoulos SE, Kleerekoper M et al. In: Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 8th ed. Ames, Iowa, USA: John Wiley & Sons, 2013:343?347.
  19. Seriolo B, Paolino S, Casabella A et al. Osteoporosis in the elderly. Aging Clin Exp Res 2013;25(suppl 1):S27?29.
  20. Reid IR. Overview of pathogenesis. In: Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Ames, Iowa, USA: John Wiley & Sons, 2013:357?360.
  21. Baxter MA, Wynn RF, Jowitt SN et al. Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. STEM CELLS 2004;22:675?682.
  22. Nishida S, Endo N, Yamagiwa H et al. Number of osteoprogenitor cells in human bone marrow markedly decreases after skeletal maturation. J Bone Miner Metab 1999;17:171?177.
  23. Muschler GF, Nitto H, Boehm CA et al. Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res 2001;19:117?125.
  24. Bellantuono I, Aldahmash A, Kassem M. Aging of marrow stromal (skeletal) stem cells and their contribution to age-related bone loss. Biochim Biophys Acta 2009;1792:364?370.
  25. Chan CKF, Seo EY, Chen JY et al. Identification and specification of the mouse skeletal stem cell. Cell 2015;160:285?298.
  26. Worthley DL, Churchill M, Compton JT et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 2015; 160:269?284.
  27. Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab ,2010.21:369?374.
  28. Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinol Metab Clin North Am 2005; 34:1015?1030, xi.
  29. Stroup J, Kane MP, Abu-Baker AM. Teriparatide in the treatment of osteoporosis. Am J Health Syst Pharm 2008; 65:532?539.
  30. Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis.N Engl J Med 2007;357:905?916.
  31. Shimomura, Shimizu H., Kobayashi I., Kobayashi S. Importance of feeding time in pair-fed, ovariectomized rats. Physiology & Behavior.1989, 45(6):1197-1200.
  32. Lasota A, Danowska-Klonowska D. Experimental osteoporosis- different methods of ovariectomy in female white rats. Annales Academiae Medicae Bialostocensis. 2004; 49: Suppl. 1.
  33. Pytlik M., Kaczmarczyk-Sedlak I, oeliwi?ski L., Janiec W., Rymkiewicz I. Effect of concurrent administration of Alendronate sodium and Retinol on development of changes in histomorphometric parameters of bones induced by ovariectomy in rats. Pol.J.Pharmacol.2004,56,571-579.
  34. Kiernan J.,?Hu S.,?Grynpas MD.,?Davies JE.,?Stanford WL., Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis. Stem Cells Transl Med.2016 May; 5(5):683-93.
  35. Bancroft J.D. and Cook H.C.: Immunohistochemistry. In: Manual of histological techniques and diagnostic applications.1994,Churchill Livingstone, Edinburgh, London, Madrid, Melbourne, New York, Tokyo, pp. 236?325.
  36. Fernandes CE. Osteoporose. Rev Bras Med. 1998; 54:37-48.
  37. Sarugaser R, Hanoun L, Keating A et al. Human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy. PLoS One 2009;4:e6498.
  38. Owen M, Friedenstein AJ. Stromal stem cells: Marrow-derived osteogenic precursors. Ciba Found Symp 1988;136:42?60. // &//Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143?147.
  39. Omi, Ezawa I.The effect of ovariectomy on bone metabolism in rats.Department of Food Nutrition, School of Home-Economics, Japan Women's University, Japa.Oct.1995 17(4):?S163?S168.
  40. Kennedy OD,?Brennan O,?Rackard SM,?Staines A,?O'Brien FJ,?Taylor D,?Lee TC. Effects of ovariectomy on bone turnover, porosity, and biomechanical properties in ovine compact bone 12 months postsurgery.J Orthop Res.2009 Mar; 27(3):303-9.
  41. Ejiri S, ?Toyooka, ?Tanaka M.,Anwar RB., Kohno S. Histological and histomorphometrical changes in rat alveolar bone following antagonistic tooth extraction and/or ovariectomy. Archives of Oral Biology Volume 51, Issue 11, November 2006, Pages 941-950.
  42. Jau-Yi Li,Hesham Tawfeek,?Brahmchetna Bedi,?Xiaoying Yang,?Jonathan Adams,?Kristy Y. Gao,Majd Zayzafoon,? Neale Weitzmann,?and?Roberto Pacifici.Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc Natl Acad Sci U S A. 2011 Jan 11; 108(2): 768?773.
  43. Hongwang Cui,?Yongjun Zhu and?Dianming Jiang.The RIP1?RIP3 Complex Mediates Osteocyte Necroptosis after Ovariectomy in Rats. PLoS One. 2016; 11(3): e0150805.
  44. Yoneda N, Saito S, Kimura M, Yamada M, Iida M, Murakani T, et al. The influence of ovariectomy on ob gene expression in rats. Horm Metab Res 1998;30:263?5.
  45. Chen Y, Heiman ML. Increased weight gain after ovariectomy is not a consequence of leptin resistance. Am J Physiol Endocrinol Metab 2001;280:E315?22.
  46. Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL 2005 Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 146:1226?1235.
  47. Demer LL and Tintut Y, Mechanisms linking osteoporosis with cardiovascular calcification. Curr Osteoporos Rep.2009 Jul;7(2):42-6.
  48. Hamerman D., Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies. 2005 Jul; 98(7):467-84.
  49. Bloomfield SA.,?Hogan HA.,?Delp MD. Decreases in bone blood flow and bone material properties in aging Fischer-344 rats. Clin Orthop Relat Res.2002 Mar;(396):248-57.
  50. Sugata Y., Sotome S., Yuasa M., Hirano M., Shinomiya K.,Okawa A.Effects of the systemic administration of alendronate on bone formation in a porous hydroxyapatite/collagen composite and resorption by osteoclasts in a bone defect model in The bone and joint journal, Apr 2011.
  51. Xiong H1,?Wei L,?Hu Y,?Zhang C,?Peng B. Effect of alendronate on alveolar bone resorption and angiogenesis in rats with experimental periapical lesions. Int Endod J.?2010 Jun;43(6):485-91.
  52. Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action (Perspectives). J Clin Invest 1996;97:2692?6.
  53. Russell RG 2006 Bisphosphonates: From bench to bedside.Ann N Y Acad Sci 1068:367?401.
  54. Gao J, Dennis JE, Muzic RF et al. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001;169:12?20.
  55. Takigami H,?Kumagai K,?Latson L,?Togawa D,?Bauer T,?Powell K,?Butler RS,?Muschler GF. Bone formation following OP-1 implantation is improved by addition of autogenous bone marrow cells in a canine femur defect model. J Orthop Res.2007 Oct;25(10):1333-42
  56. Zenhaeusern G,?Gubser P,?Eisele P,?Gasser O,?Steinhuber A,?Trampuz A,?Handschin C,?Luster AD,?Hess C. A high-mobility, low-cost phenotype defines human effector-memory CD8+ T cells.B 2009 Jan 1;113(1):95-9. doi: 10.1182/blood-2008-04-153262.
  57. Oshita Koichi, Kunihiro Yamaoka, Nobuyuki Udagawa, Shunsuke Fukuyo, Koshiro Sonomoto, Keisuke Maeshima et al. Human Mesenchymal Stem Cells Inhibit Osteoclastogenesis Through Osteoprotegerin Production. American College of Rheumatology 2011; 63 1658?1667.
  58. Gutwald R, Haberstroh J, Kuschnierz J et al. Mesenchymal stem cells and inorganic bovine bone mineral in sinus augmentation: Comparison with augmentation by autologous bone in adult sheep. Br J Oral Maxillofac Surg 2010;48:285?290.
  59. Longobardi L, Granero-Molto F, O?Rear L et al. Subcellular localization of IRS-1 in IGF-I-mediated chondrogenic proliferation, differentiation and hypertrophy of bone marrow mesenchymal stem cells.Growth Factors 2009;27:309?320.
  60. Chapel A, Bertho JM, Bensidhoum M et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med 2003;5:1028?1038.
  61. Granero-Molto F, Weis JA, Miga MI et al. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells 2009;27:1887?1898.
  62. Meyerrose TE, De Ugarte DA, Hofling AA et al. In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells 2007;25:220?227.
  63. Lecka-Czernik B, Gubrij I?,Moerman ?E, Kajkenova O, Lipschitz D, Manolagas ?S,Jilka RL 1999 Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPAR γ2. J Cell Biochem 74:357?371.

[Marwa M. Abd El Hameed and Iman A. Fathy. (2018); EFFECT OF BONE MARROW DERIVED MESENCHYMAL STEM CELLS VS ALENDRONATE SODIUM IN TREATMENT OF INDUCED ESTROGEN DEFICIENCY OSTEOPOROSIS IN ALVEOLAR BONE OF ALBINO RATS. Int. J. of Adv. Res. 6 (Apr). 677-689] (ISSN 2320-5407). www.journalijar.com


Iman A. Fathy
lecturer of oral biology, Faculty of dentistry, Ain Shams university, Egypt.

DOI:


Article DOI: 10.21474/IJAR01/6902      
DOI URL: https://dx.doi.org/10.21474/IJAR01/6902