Osteoporosis, periodontal and other diseases share a risk factor – low vitamin D – March 2022

Osteoporosis and periodontal diseases - An update on their association and mechanistic links

Review Periodontol 2000. 2022 Mar 4. doi: 10.1111/prd.12422 behind paywall
Bo Yu 1, Cun-Yu Wang 2 3

Periodontitis and osteoporosis are prevalent inflammation-associated skeletal disorders that pose significant public health challenges to our aging population. Both periodontitis and osteoporosis are bone disorders closely associated with inflammation and aging. There has been consistent intrigue on whether a systemic skeletal disease such as osteoporosis will amplify the alveolar bone loss in periodontitis. A survey of the literature published in the past 25 years indicates that systemic low bone mineral density (BMD) is associated with alveolar bone loss, while recent evidence also suggests a correlation between clinical attachment loss and other parameters of periodontitis. Inflammation and its influence on bone remodeling play critical roles in the pathogenesis of both osteoporosis and periodontitis and could serve as the central mechanistic link between these disorders. Enhanced cytokine production and elevated inflammatory response exacerbate osteoclastic bone resorption while inhibiting osteoblastic bone formation, resulting in a net bone loss. With aging, accumulation of oxidative stress and cellular senescence drive the progression of osteoporosis and exacerbation of periodontitis.
Vitamin D deficiency and smoking are shared risk factors and may mediate the connection between osteoporosis and periodontitis, through increasing oxidative stress and impairing host response to inflammation. With the connection between systemic and localized bone loss in mind, routine dental exams and intraoral radiographs may serve as a low-cost screening tool for low systemic BMD and increased fracture risk.
Conversely, patients with fracture risk beyond the intervention threshold are at greater risk for developing severe periodontitis and undergo tooth loss. Various Food and Drug Administration-approved therapies for osteoporosis have shown promising results for treating periodontitis. Understanding the molecular mechanisms underlying their connection sheds light on potential therapeutic strategies that may facilitate co-management of systemic and localized bone loss.

References

  1. Demmer RT, Papapanou PN. Epidemiologic patterns of chronic and aggressive periodontitis. Periodontol 2000. 2010;53:28-44.
  2. American Academy of Periodontology Task Force Report on the Update to the 1999 Classification of Periodontal Diseases and Conditions. J Periodontol. 1999;2015(86):835-838.
  3. Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol. 1996;67:1041-1049.
  4. Eke PI, Thornton-Evans GO, Wei L, Borgnakke WS, Dye BA, Genco RJ. Periodontitis in US adults: national health and nutrition examination survey 2009-2014. J Am Dent Assoc. 2018;149:576-588.e576.
  5. Reginster JY, Burlet N. Osteoporosis: a still increasing prevalence. Bone. 2006;38:S4-9.
  6. Kawai M, Modder UI, Khosla S, Rosen CJ. Emerging therapeutic opportunities for skeletal restoration. Nat Rev Drug Discov. 2011;10:141-156.
  7. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Mineral Res. 2007;22:465-475.
  8. Groen JJ, Duyvensz F, Halsted JA. Diffuse alveolar atrophy of the jaw (non-inflammatory form of paradental disease) and pre-senile osteoporosis. Gerontol Clin. 1960;2:68-86.
  9. Armitage GC. Development of a classification system for periodontal diseases and conditions. Northwest Dent. 2000;79:31-35.
  10. Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: Framework and proposal of a new classification and case definition. J Periodontol. 2018;89(Suppl 1):S159-s172.
  11. Caton JG, Armitage G, Berglundh T, et al. A new classification scheme for periodontal and peri-implant diseases and conditions - Introduction and key changes from the 1999 classification. J Periodontol. 2018;89(Suppl 1):s1-s8.
  12. Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol. 2011;164:9-16.
  13. Vieira AR, Albandar JM. Role of genetic factors in the pathogenesis of aggressive periodontitis. Periodontol 2000. 2014;65:92-106.
  14. Albandar JM, Susin C, Hughes FJ. Manifestations of systemic diseases and conditions that affect the periodontal attachment apparatus: Case definitions and diagnostic considerations. J Periodontol. 2018;89(Suppl 1):s183-s203.
  15. Papapanou PN, Sanz M, Buduneli N, et al. Periodontitis: consensus report of workgroup 2 of the 2017 world workshop on the classification of periodontal and peri-implant diseases and conditions. J Clin Periodontol. 2018;45:S162-S170.
  16. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet (London, England). 2002;359:1929-1936.
  17. Okabe S, Morimoto Y, Ansai T, et al. Assessment of the relationship between the mandibular cortex on panoramic radiographs and the risk of bone fracture and vascular disease in 80-year-olds. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:433-442.
  18. Brennan RM, Genco RJ, Hovey KM, Trevisan M, Wactawski-Wende J. Clinical attachment loss, systemic bone density, and subgingival calculus in postmenopausal women. J Periodontol. 2007;78:2104-2111.
  19. Ishii K, Taguchi A, Nakamoto T, et al. Diagnostic efficacy of alveolar bone loss of the mandible for identifying postmenopausal women with femoral osteoporosis. Dentomaxillofac Radiol. 2007;36:28-33.
  20. Taguchi A, Ohtsuka M, Tsuda M, et al. Risk of vertebral osteoporosis in post-menopausal women with alterations of the mandible. Dentomaxillofac Radiol. 2007;36:143-148.
  21. Takaishi Y, Okamoto Y, Ikeo T, et al. Correlations between periodontitis and loss of mandibular bone in relation to systemic bone changes in postmenopausal Japanese women. Osteoporos Int. 2005;16:1875-1882.
  22. Hildebolt CF, Pilgram TK, Yokoyama-Crothers N, et al. The pattern of alveolar crest height change in healthy postmenopausal women after 3 years of hormone/estrogen replacement. Therapy. 2002;73:1279-1284.
  23. Jonasson G, Bankvall G, Kiliaridis S. Estimation of skeletal bone mineral density by means of the trabecular pattern of the alveolar bone, its interdental thickness, and the bone mass of the mandible. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol. 2001;92:346-352.
  24. Tezal M, Wactawski-Wende J, Grossi SG, Ho AW, Dunford R, Genco RJ. The relationship between bone mineral density and periodontitis in postmenopausal women. J Periodontol. 2000;71:1492-1498.
  25. Taguchi A, Suei Y, Ohtsuka M, Otani K, Tanimoto K, Hollender LG. Relationship between bone mineral density and tooth loss in elderly Japanese women. Dentomaxillofac Radiol. 1999;28:219-223.
  26. Payne JB, Reinhardt RA, Nummikoski PV, Patil KD. Longitudinal alveolar bone loss in postmenopausal osteoporotic/osteopenic women. Osteoporos Int. 1999;10:34-40.
  27. Hausmann E, Allen K, Carpio L, Christersson LA, Clerehugh V. Computerized methodology for detection of alveolar crestal bone loss from serial intraoral radiographs. J Periodontol. 1992;63:657-662.
  28. von Wowern N. Bone mass of mandibles. In vitro and in vivo analyses. Dan Med Bull. 1986;33:23-44.
  29. Horner K, Devlin H, Harvey L. Detecting patients with low skeletal bone mass. J Dent. 2002;30:171-175.
  30. Devlin H, Allen PD, Graham J, et al. Automated osteoporosis risk assessment by dentists: a new pathway to diagnosis. Bone. 2007;40:835-842.
  31. Jonasson G, Sundh V, Hakeberg M, Hassani-Nejad A, Lissner L, Ahlqwist M. Mandibular bone changes in 24 years and skeletal fracture prediction. Clin Oral Invest. 2013;17:565-572.
  32. Jonasson G, Sundh V, Ahlqwist M, Hakeberg M, Björkelund C, Lissner L. A prospective study of mandibular trabecular bone to predict fracture incidence in women: a low-cost screening tool in the dental clinic. Bone. 2011;49:873-879.
  33. Hassani-Nejad A, Ahlqwist M, Hakeberg M, Jonasson G. Mandibular trabecular bone as fracture indicator in 80-year-old men and women. Eur J Oral Sci. 2013;121:525-531.
  34. Lindh C, Horner K, Jonasson G, et al. The use of visual assessment of dental radiographs for identifying women at risk of having osteoporosis: the OSTEODENT project. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:285-293.
  35. Jonasson G, Jonasson L, Kiliaridis S. Skeletal bone mineral density in relation to thickness, bone mass, and structure of the mandibular alveolar process in dentate men and women. Eur J Oral Sci. 2007;115:117-123.
  36. Lindh C, Obrant K, Petersson A. Maxillary bone mineral density and its relationship to the bone mineral density of the lumbar spine and hip. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98:102-109.
  37. Elders PJ, Habets LL, Netelenbos JC, van der Linden LW, van der Stelt PF. The relation between periodontitis and systemic bone mass in women between 46 and 55 years of age. J Clin Periodontol. 1992;19:492-496.
  38. Jacobs R, Ghyselen J, Koninckx P, van Steenberghe D. Long-term bone mass evaluation of mandible and lumbar spine in a group of women receiving hormone replacement therapy. Eur J Oral Sci. 1996;104:10-16.
  39. Mashalkar VN, Suragimath G, Zope SA, Varma SA. A cross-sectional study to assess and correlate osteoporosis and periodontitis among postmenopausal women: a dual energy X-ray absorptiometry study. J Mid-Life Health. 2018;9:2-7.
  40. Passos-Soares JS, Vianna MIP, Gomes-Filho IS, et al. Association between osteoporosis treatment and severe periodontitis in postmenopausal women. Menopause (New York, NY). 2017;24:789-795.
  41. Penoni DC, Torres SR, Farias ML, Fernandes TM, Luiz RR, Leão AT. Association of osteoporosis and bone medication with the periodontal condition in elderly women. Osteoporos Int. 2016;27:1887-1896.
  42. Juluri R, Prashanth E, Gopalakrishnan D, et al. Association of postmenopausal osteoporosis and periodontal disease: a double-blind case-control study. J Int Oral Health. 2015;7:119-123.
  43. Singh A, Sharma RK, Siwach RC, Tewari S, Narula SC. Association of bone mineral density with periodontal status in postmenopausal women. J Invest Clin Dent. 2014;5:275-282.
  44. Tak I-H, Shin M-H, Kweon S-S, et al. The association between periodontal disease, tooth loss and bone mineral density in a Korean population. J Clin Periodontol. 2014;41:1139-1144.
  45. Gondim V, Aun J, Fukuda CT, et al. Severe loss of clinical attachment level: an independent association with low hip bone mineral density in postmenopausal females. J Periodontol. 2013;84:352-359.
  46. Passos JS, Vianna MI, Gomes-Filho IS, et al. Osteoporosis/osteopenia as an independent factor associated with periodontitis in postmenopausal women: a case-control study. Osteoporos Int. 2013;24:1275-1283.
  47. Iwasaki M, Taylor GW, Nakamura K, Yoshihara A, Miyazaki H. Association between low bone mineral density and clinical attachment loss in Japanese postmenopausal females. J Periodontol. 2013;84:1708-1716.
  48. Marjanovic EJ, Southern HN, Coates P, et al. Do patients with osteoporosis have an increased prevalence of periodontal disease? A cross-sectional study. Osteoporos Int. 2013;24:1973-1979.
  49. Moeintaghavi A, Pourjavad M, Dadgar S, Tabbakh NS. Evaluation of the association between periodontal parameters, osteoporosis and osteopenia in post menopausal women. J Dent (Tehran, Iran). 2013;10:443-448.
  50. Grocholewicz K, Bohatyrewicz A. Oral health and bone mineral density in postmenopausal women. Arch Oral Biol. 2012;57:245-251.
  51. Al Habashneh R, Alchalabi H, Khader YS, Hazza'a AM, Odat Z, Johnson GK. Association between periodontal disease and osteoporosis in postmenopausal women in Jordan. J Periodontol. 2010;81:1613-1621.
  52. Gomes-Filho IS, Passos JDS, Cruz SS, et al. The association between postmenopausal osteoporosis and periodontal disease. J Periodontol. 2007;78:1731-1740.
  53. Taguchi A, Fujiwara S, Masunari N, Suzuki G. Self-reported number of remaining teeth is associated with bone mineral density of the femoral neck, but not of the spine, in Japanese men and women. Osteoporos Int. 2004;15:842-846.
  54. Mohammad AR, Hooper DA, Vermilyea SG, Mariotti A, Preshaw PM. An investigation of the relationship between systemic bone density and clinical periodontal status in post-menopausal Asian-American women. Int Dent J. 2003;53:121-125.
  55. Pilgram TK, Hildebolt CF, Dotson M, et al. Relationships between clinical attachment level and spine and hip bone mineral density: data from healthy postmenopausal women. J Periodontol. 2002;73:298-301.
  56. Lundström A, Jendle J, Stenström B, Toss G, Ravald N. Periodontal conditions in 70-year-old women with osteoporosis. Swed Dent J. 2001;25:89-96.
  57. Weyant RJ, Pearlstein ME, Churak AP, Forrest K, Famili P, Cauley JA. The association between osteopenia and periodontal attachment loss in older women. J Periodontol. 1999;70:982-991.
  58. Mohammad AR, Bauer RL, Yeh CK. Spinal bone density and tooth loss in a cohort of postmenopausal women. Int J Prosthodont. 1997;10:381-385.
  59. Hildebolt CF, Pilgram TK, Dotson M, et al. Attachment loss with postmenopausal age and smoking. J Periodont Res. 1997;32:619-625.
  60. Mohammad AR, Brunsvold M, Bauer R. The strength of association between systemic postmenopausal osteoporosis and periodontal disease. Int J Prosthodont. 1996;9:479-483.
  61. Penoni DC, Fidalgo TK, Torres SR, et al. Bone density and clinical periodontal attachment in postmenopausal women: a systematic review and meta-analysis. J Dent Res. 2017;96:261-269.
  62. Martínez-Maestre M, González-Cejudo C, Machuca G, Torrejón R, Castelo-Branco C. Periodontitis and osteoporosis: a systematic review. Climacteric. 2010;13:523-529.
  63. Nicopoulou-Karayianni K, Tzoutzoukos P, Mitsea A, et al. Tooth loss and osteoporosis: the OSTEODENT study. J Clin Periodontol. 2009;36:190-197.
  64. Krall EA, Garcia RI, Dawson-Hughes B. Increased risk of tooth loss is related to bone loss at the whole body, hip, and spine. Calcif Tissue Int. 1996;59:433-437.
  65. Drozdzowska B, Pluskiewicz W, Michno M. Tooth count in elderly women in relation to their skeletal status. Maturitas. 2006;55:126-131.
  66. Krall EA, Dawson-Hughes B, Papas A, Garcia RI. Tooth loss and skeletal bone density in healthy postmenopausal women. Osteoporos Int. 1994;4:104-109.
  67. May H, Reader R, Murphy S, Khaw KT. Self-reported tooth loss and bone mineral density in older men and women. Age Ageing. 1995;24:217-221.
  68. Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol. 2014;35:3-11.
  69. Yu B, Wang C-Y. Osteoporosis: the result of an ‘aged’ bone microenvironment. Trends Mol Med. 2016;22:641-644.
  70. Graves D. Cytokines that promote periodontal tissue destruction. J Periodontol. 2008;79:1585-1591.
  71. Sczepanik FSC, Grossi ML, Casati M, et al. Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol 2000. 2020;84:45-68.
  72. Mahanonda R, Pichyangkul S. Toll-like receptors and their role in periodontal health and disease. Periodontol 2000. 2007;43(1):41-55.
  73. Kawai T, Matsuyama T, Hosokawa Y, et al. B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. Am J Pathol. 2006;169:987-998.
  74. Teng Y-TA, Nguyen H, Gao X, et al. Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection. J Clin Investig. 2000;106:R59-R67.
  75. Pacios S, Xiao W, Mattos M, et al. Osteoblast lineage cells play an essential role in periodontal bone loss through activation of nuclear factor-kappa B. Sci Rep. 2015;5:16694.
  76. Chang J, Wang Z, Tang E, et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med. 2009;15:682-689.
  77. Jimi E, Aoki K, Saito H, et al. Selective inhibition of NF-kappaB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat Med. 2004;10:617-624.
  78. Redlich K, Görtz B, Hayer S, et al. Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis. Am J Pathol. 2004;164:543-555.
  79. Haugeberg G, Conaghan PG, Quinn M, Emery P. Bone loss in patients with active early rheumatoid arthritis: infliximab and methotrexate compared with methotrexate treatment alone. Explorative analysis from a 12-month randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2009;68:1898-1901.
  80. Ghosh S, Karin M. Missing Pieces in the NF-?B Puzzle. Cell. 2002;109(2):S81-S96.
  81. Wang CY, Guttridge DC, Mayo MW, Baldwin AS Jr. NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol. 1999;19:5923-5929.
  82. Wang CY, Mayo MW, Baldwin AS Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science. 1996;274:784-787.
  83. Franzoso G, Carlson L, Xing L, et al. Requirement for NF-?B in osteoclast and B-cell development. Genes & Development. 1997;11(24):3482-3496.
  84. Ruocco MG, Maeda S, Park JM, et al. I?B kinase (IKK)ß, but not IKKa, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J Exp Med. 2005;201:1677-1687.
  85. Lee HJ, Kang IK, Chung CP, Choi SM. The subgingival microflora and gingival crevicular fluid cytokines in refractory periodontitis. J Clin Periodontol. 1995;22:885-890.
  86. Delima AJ, Karatzas S, Amar S, Graves DT. Inflammation and tissue loss caused by periodontal pathogens is reduced by interleukin-1 antagonists. J Infect Dis. 2002;186:511-516.
  87. Chiang CY, Kyritsis G, Graves DT, Amar S. Interleukin-1 and tumor necrosis factor activities partially account for calvarial bone resorption induced by local injection of lipopolysaccharide. Infect Immun. 1999;67:4231-4236.
  88. Dayan S, Stashenko P, Niederman R, Kupper TS. Oral epithelial overexpression of IL-1alpha causes periodontal disease. J Dent Res. 2004;83:786-790.
  89. Gaspersic R, Stiblar-Martincic D, Osredkar J, Skaleric U. Influence of subcutaneous administration of recombinant TNF-alpha on ligature-induced periodontitis in rats. J Periodontal Res. 2003;38:198-203.
  90. Garlet GP, Cardoso CRB, Campanelli AP, et al. The dual role of p55 tumour necrosis factor-a receptor in Actinobacillus actinomycetemcomitans-induced experimental periodontitis: host protection and tissue destruction. Clin Exp Immuno. 2006;147(1):128-138.
  91. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-a induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106:1481-1488.
  92. Pacifici R, Rifas L, McCracken R, Avioli LV. The role of interleukin-1 in postmenopausal bone loss. Exp Gerontol. 1990;25:309-316.
  93. Barbour KE, Lui LY, Ensrud KE, et al. Inflammatory markers and risk of hip fracture in older white women: the study of osteoporotic fractures. J Bone Mineral Res. 2014;29:2057-2064.
  94. Pacifici R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Mineral Res. 1996;11:1043-1051.
  95. Hajishengallis G, Reis ES, Mastellos DC, Ricklin D, Lambris JD. Novel mechanisms and functions of complement. Nat Immunol. 2017;18:1288-1298.
  96. Zhang X, Kimura Y, Fang C, et al. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood. 2007;110:228-236.
  97. Hajishengallis G, Kajikawa T, Hajishengallis E, et al. Complement-dependent mechanisms and interventions in periodontal disease. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.00406
  98. Courts FJ, Boackle RJ, Fudenberg HH, Silverman M. Detection of functional complement components in gingival crevicular fluid from humans with periodontal disease. J Dent Res. 1977;56:327-331.
  99. Patters M, Niekrash C, Lang NP. Assessment of complement cleavage in gingival fluid during experimental gingivitis in man. J Clin Periodontol. 1989;16:33-37.
  100. Niekrash CE, Patters MR. Simultaneous assessment of complement components C3, C4, and B and their cleavage products in human gingival fluid: II. Longitudinal changes during periodontal therapy. J Periodontal Res. 1985;20:268-275.
  101. Maekawa T, Abe T, Hajishengallis E, et al. Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. J Immunol. 2014;192:6020.
  102. MacKay DL, Kean TJ, Bernardi KG, et al. Reduced bone loss in a murine model of postmenopausal osteoporosis lacking complement component 3. J Orthopaedic Res. 2018;3(36):118-128.
  103. Matsuo K, Owens JM, Tonko M, Elliott C, Chambers TJ, Wagner EF. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Genet. 2000;24:184-187.
  104. Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11:234-250.
  105. Takayanagi H, Kim S, Koga T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3:889-901.
  106. Teitelbaum SL. Osteoclasts: what do they do and how do they do it? Am J Pathol. 2007;170:427-435.
  107. Lee SK, Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology. 1999;140:3552-3561.
  108. Horwood NJ, Elliott J, Martin TJ, Gillespie MT. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology. 1998;139:4743-4746.
  109. Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD. Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood. 2001;97:3349-3353.
  110. Gilbert L, He X, Farmer P, et al. Expression of the osteoblast differentiation factor RUNX2 (Cbfa1/AML3/Pebp2aA) is inhibited by tumor necrosis factor-a. J Biol Chem. 2002;277:2695-2701.
  111. Kaneki H, Guo R, Chen D, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem. 2006;281:4326-4333.
  112. Chang J, Liu F, Lee M, et al. NF-kappaB inhibits osteogenic differentiation of mesenchymal stem cells by promoting beta-catenin degradation. Proc Natl Acad Sci USA. 2013;110:9469-9474.
  113. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156-163.
  114. Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280:19883-19887.
  115. Mundy GR. Osteoporosis and inflammation. Nutr Rev. 2007;65:S147-S151.
  116. Ginaldi L, Di Benedetto M, De Martinis M. Osteoporosis, inflammation and ageing. Immun Ageing. 2005;2:14.
  117. Lin CL, Moniz C, Chambers TJ, Chow JW. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology. 1996;111:1263-1271.
  118. Khosla S, Melton LJ 3rd, Riggs BL. The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? J Bone Mineral Res. 2011;26:441-451.
  119. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194-1217.
  120. Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab. 2010;21:369-374.
  121. Tilstra JS, Robinson AR, Wang J, et al. NF-?B inhibition delays DNA damage-induced senescence and aging in mice. J Clin Investig. 2012;122:2601-2612.
  122. Yu B, Huo L, Liu Y, et al. PGC-1a controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell. 2018;23:193-209.e195.
  123. Persson GR. Periodontal complications with age. Periodontol 2000. 2018;78(1):185-194.
  124. Papapanou PN, Lindhe J. Preservation of probing attachment and alveolar bone levels in 2 random population samples. J Clin Periodontol. 1992;19:583-588.
  125. Hajishengallis G. Aging and its impact on innate immunity and inflammation: implications for periodontitis. J Oral Biosci. 2014;56:30-37.
  126. Wu Y, Dong G, Xiao W, et al. Effect of aging on periodontal inflammation, microbial colonization, and disease susceptibility. J Dent Res. 2016;95:460-466.
  127. Bodineau A, Folliguet M, Séguier S. Tissular senescence and modifications of oral ecosystem in the elderly: risk factors for mucosal pathologies. Curr Aging Sci. 2009;2:109-120.
  128. Fransson C, Mooney J, Kinane DF, Berglundh T. Differences in the inflammatory response in young and old human subjects during the course of experimental gingivitis. J Clin Periodontol. 1999;26:453-460.
  129. Ebersole JL, Steffen MJ, Gonzalez-Martinez J, Novak MJ. Effects of age and oral disease on systemic inflammatory and immune parameters in nonhuman primates. Clin Vaccine Immunol CVI. 2008;15:1067-1075.
  130. Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocrinol Rev. 2010;31:266-300.
  131. Newmeyer DD, Ferguson-Miller S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell. 2003;112:481-490.
  132. Almeida M, Han L, Martin-Millan M, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282:27285-27297.
  133. Goettsch C, Babelova A, Trummer O, et al. NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis. J Clin Invest. 2013;123:4731-4738.
  134. Lean JM, Davies JT, Fuller K, et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest. 2003;112:915-923.
  135. Bartell SM, Kim H-N, Ambrogini E, et al. FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat Commun. 2014;5:3773.
  136. Ambrogini E, Almeida M, Martin-Millan M, et al. FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab. 2010;11:136-146.
  137. Cervellati C, Bonaccorsi G, Cremonini E, et al. Oxidative stress and bone resorption interplay as a possible trigger for postmenopausal osteoporosis. Biomed Res Int. 2014;2014:569563.
  138. Chapple IL, Matthews J. The role of reactive oxygen and antioxidant species in periodontal tissue destruction. Periodontol 2000. 2007;43:160-232.
  139. Wang Y, Andrukhov O, Rausch-Fan X. Oxidative stress and antioxidant system in periodontitis. Front Physiol. 2017;8:910.
  140. Chapple IL, Matthews JB. The role of reactive oxygen and antioxidant species in periodontal tissue destruction. Periodontol 2000. 2007;43(1):160-232.
  141. Konopka T, Król K, Kopec W, Gerber H. Total antioxidant status and 8-hydroxy-2'-deoxyguanosine levels in gingival and peripheral blood of periodontitis patients. Arch Immunol Ther Exp. 2007;55:417-422.
  142. Su H, Gornitsky M, Velly AM, Yu H, Benarroch M, Schipper HM. Salivary DNA, lipid, and protein oxidation in nonsmokers with periodontal disease. Free Radic Biol Med. 2009;46:914-921.
  143. Löe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care. 1993;16:329-334.
  144. Aquino-Martinez R, Rowsey JL, Fraser DG, et al. LPS-induced premature osteocyte senescence: Implications in inflammatory alveolar bone loss and periodontal disease pathogenesis. Bone. 2020;132:115220.
  145. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232-236.
  146. Farr JN, Xu M, Weivoda MM, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017;23:1072-1079.
  147. Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes. 2015;64:2289-2298.
  148. Zhou Bo O, Yue R, Murphy Malea M, Peyer JG, Morrison SJ. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. 2014;15:154-168.
  149. Bianco P, Cao X, Frenette PS, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19:35-42.
  150. Bianco P, Robey PG. Skeletal stem cells. Development. 2015;142:1023-1027.
  151. Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med. 2014;20:870.
  152. Li H, Liu P, Xu S, et al. FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging. J Clin Invest. 2017;127:1241-1253.
  153. Liu W, Zhang L, Xuan K, et al. Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells. Bone Res. 2018;6:27.
  154. Farr JN, Fraser DG, Wang H, et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res. 2016;31:1920-1929.
  155. Kim HN, Chang J, Iyer S, et al. Elimination of senescent osteoclast progenitors has no effect on the age-associated loss of bone mass in mice. Aging Cell. 2019;18:e12923.
  156. Pignolo RJ, Samsonraj RM, Law SF, Wang H, Chandra A. Targeting cell senescence for the treatment of age-related bone loss. Curr Osteoporos Rep. 2019;17:70-85.
  157. Zhang P, Wang Q, Nie L, et al. Hyperglycemia-induced inflamm-aging accelerates gingival senescence via NLRC4 phosphorylation. J Biol Chem. 2019;294:18807-18819.
  158. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. J Am Med Assoc. 2005;293:2257-2264.
  159. Shimazaki Y, Shirota T, Uchida K, et al. Intake of dairy products and periodontal disease: the Hisayama Study. J Periodontol. 2008;79:131-137.
  160. Al-Zahrani MS. Increased intake of dairy products is related to lower periodontitis prevalence. J Periodontol. 2006;77:289-294.
  161. Yoshida T, Stern PH. How vitamin D works on bone. Endocrinol Metab Clin North Am. 2012;41:557-569.
  162. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med. 2004;116:634-639.
  163. Laird E, Ward M, McSorley E, Strain JJ, Wallace J. vitamin D and bone health: potential mechanisms. Nutrients. 2010;2:693-724.
  164. Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature. 1992;355:446-449.
  165. Takahashi N, Udagawa N, Suda T. vitamin D endocrine system and osteoclasts. Bonekey Rep. 2014;3:495.
  166. Zarei A, Morovat A, Javaid K, Brown CP. vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts. Bone Res. 2016;4:16030.
  167. Baldock PA, Thomas GP, Hodge JM, et al. vitamin D action and regulation of bone remodeling: suppression of osteoclastogenesis by the mature osteoblast. J Bone Miner Res. 2006;21:1618-1626.
  168. Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest. 1999;104:439-446.
  169. Müller K, Haahr PM, Diamant M, Rieneck K, Kharazmi A, Bendtzen K. 1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level. Cytokine. 1992;4:506-512.
  170. Inanir A, Ozoran K, Tutkak H, Mermerci B. The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis. J Int Med Res. 2004;32:570-582.
  171. Grossi SG, Genco RJ, Machtei EE, et al. Assessment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol. 1995;66:23-29.
  172. Kanis JA, Johnell O, Oden A, et al. smoking and fracture risk: a meta-analysis. Osteoporos Int. 2005;16:155-162.
  173. Giannopoulou C, Kamma JJ, Mombelli A. Effect of inflammation, smoking and stress on gingival crevicular fluid cytokine level. J Clin Periodontol. 2003;30:145-153.
  174. Tymkiw KD, Thunell DH, Johnson GK, et al. Influence of smoking on gingival crevicular fluid cytokines in severe chronic periodontitis. J Clin Periodontol. 2011;38:219-228.
  175. Buduneli N, Buduneli E, Kütükçüler N. Interleukin-17, RANKL, and osteoprotegerin levels in gingival crevicular fluid from smoking and non-smoking patients with chronic periodontitis during initial periodontal treatment. J Periodontol. 2009;80:1274-1280.
  176. César-Neto JB, Duarte PM, de Oliveira MC, Tambeli CH, Sallum EA, Nociti FH Jr. smoking modulates interleukin-6:interleukin-10 and RANKL:osteoprotegerin ratios in the periodontal tissues. J Periodontal Res. 2007;42:184-191.
  177. Lappin DF, Sherrabeh S, Jenkins WM, Macpherson LM. Effect of smoking on serum RANKL and OPG in sex, age and clinically matched supportive-therapy periodontitis patients. J Clin Periodontol. 2007;34:271-277.
  178. Tang TH, Fitzsimmons TR, Bartold PM. Effect of smoking on concentrations of receptor activator of nuclear factor kappa B ligand and osteoprotegerin in human gingival crevicular fluid. J Clin Periodontol. 2009;36:713-718.
  179. Aziz AS, Kalekar MG, Suryakar AN, et al. Assessment of some biochemical oxidative stress markers in male smokers with chronic periodontitis. Indian J Clin Biochem IJCB. 2013;28:374-380.
  180. Fredriksson MI, Figueredo CM, Gustafsson A, Bergström KG, Asman BE. Effect of periodontitis and smoking on blood leukocytes and acute-phase proteins. J Periodontol. 1999;70:1355-1360.
  181. Chang CH, Han ML, Teng NC, et al. Cigarette smoking aggravates the activity of periodontal disease by disrupting redox homeostasis- an observational study. Sci Rep. 2018;8:11055.
  182. Agnihotri R, Pandurang P, Kamath SU, et al. Association of cigarette smoking with superoxide dismutase enzyme levels in subjects with chronic periodontitis. J Periodontol. 2009;80:657-662.
  183. Al-Bashaireh AM, Haddad LG, Weaver M, Chengguo X, Kelly DL, Yoon S. The effect of tobacco smoking on bone mass: an overview of pathophysiologic mechanisms. J Osteoporos. 2018;2018:1206235.
  184. Reddy MS, Morgan SL. Decreased bone mineral density and periodontal management. Periodontol 2000. 2013;61:195-218.
  185. Penoni DC, Vettore MV, Torres SR, Farias MLF, Leão ATT. An investigation of the bidirectional link between osteoporosis and periodontitis. Arch Osteoporos. 2019;14:94.
  186. Passos-Soares JDS, Vianna MIP, Gomes-Filho IS, et al. Association between osteoporosis treatment and severe periodontitis in postmenopausal women. Menopause. 2017;24:789-795.
  187. Krall EA, Dawson-Hughes B, Hannan MT, Wilson PW, Kiel DP. Postmenopausal Estrogen Replacement and Tooth Retention. The Am J Med. 1997;102(6):536-542.
  188. Garcia MN, Hildebolt CF, Miley DD, et al. One-year effects of vitamin D and calcium supplementation on chronic periodontitis. J Periodontol. 2011;82:25-32.
  189. Dixon D, Hildebolt CF, Miley DD, et al. Calcium and vitamin D use among adults in periodontal disease maintenance programmes. Br Dent J. 2009;206:627-631.
  190. Millen AE, Andrews CA, LaMonte MJ, et al. vitamin D status and 5-year changes in periodontal disease measures among postmenopausal women: the Buffalo OsteoPerio Study. J Periodontol. 2014;85:1321-1332.
  191. Pavlesen S, Mai X, Wactawski-Wende J, et al. vitamin D status and tooth loss in postmenopausal females: the buffalo osteoporosis and periodontal disease (OsteoPerio) study. J Periodontol. 2016;87:852-863.
  192. Thorin MH, Wihlborg A, Åkesson K, Gerdhem P. smoking, smoking cessation, and fracture risk in elderly women followed for 10 years. Osteoporos Int. 2016;27:249-255.
  193. Tomar SL, Asma S. smoking-attributable periodontitis in the United States: findings from NHANES III. National Health and Nutrition Examination Survey. J Periodontol. 2000;71:743-751.
  194. Rocha M, Nava LE, Vázquez de la Torre C, Sánchez-Márin F, Garay-Sevilla ME, Malacara JM. Clinical and radiological improvement of periodontal disease in patients with type 2 diabetes mellitus treated with alendronate: a randomized, placebo-controlled trial. J Periodontol. 2001;72:204-209.
  195. Akram Z, Abduljabbar T, Kellesarian SV, Abu Hassan MI, Javed F, Vohra F. Efficacy of bisphosphonate as an adjunct to nonsurgical periodontal therapy in the management of periodontal disease: a systematic review. Br J Clin Pharmacol. 2017;83:444-454.
  196. Aghaloo TL, Kang B, Sung EC, et al. Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res. 2011;26:1871-1882.
  197. Diniz-Freitas M, Fernández-Feijoo J, Diz Dios P, Pousa X, Limeres J. Denosumab-related osteonecrosis of the jaw following non-surgical periodontal therapy: A case report. J Clin Periodontol. 2018;45:570-577.
  198. Barros SP, Silva MA, Somerman MJ, Nociti FH Jr. Parathyroid hormone protects against periodontitis-associated bone loss. J Dent Res. 2003;82:791-795.
  199. Kim JH, Kim AR, Choi YH, et al. Intermittent PTH administration improves alveolar bone formation in type 1 diabetic rats with periodontitis. J Transl Med. 2018;16:70.
  200. Yamashita J. The therapeutic potential of parathyroid hormone in dental and oral medicine. Oral Sci Int. 2020;17:3-14.
  201. Taut AD, Jin Q, Chung J-H, et al. Sclerostin antibody stimulates bone regeneration after experimental periodontitis. J Bone Miner Res. 2013;28:2347-2356.
  202. Yao Y, Kauffmann F, Maekawa S, et al. Sclerostin antibody stimulates periodontal regeneration in large alveolar bone defects. Sci Rep. 2020;10:16217.
  203. Chen H, Xu X, Liu M, et al. Sclerostin antibody treatment causes greater alveolar crest height and bone mass in an ovariectomized rat model of localized periodontitis. Bone. 2015;76:141-148.
  204. Yu SH, Hao J, Fretwurst T, et al. Sclerostin-Neutralizing Antibody Enhances Bone Regeneration Around Oral Implants. Tissue Eng Part A. 2018;24:1672-1679.

VitaminDWiki - Overview Osteoporosis and vitamin D contains

  • FACT: Bones need Calcium (this has been known for a very long time)
  • FACT: Vitamin D improves Calcium bioavailability (3X ?)
  • FACT: Should not take > 750 mg of Calcium if taking lots of vitamin D (Calcium becomes too bio-available)
  • FACT: Adding vitamin D via Sun, UV, or supplements increased vitamin D in the blood
  • FACT: Vitamin D supplements are very low cost
  • FACT: Many trials, studies. reviews, and meta-analysis agree: adding vitamin D reduces osteoporosis
  • FACT: Toxic level of vitamin D is about 4X higher than the amount needed to reduce osteoporosis
  • FACT: Co-factors help build bones.
  • FACT: Vitamin D Receptor can restrict Vitamin D from getting to many tissues, such as bones
  • It appears that to TREAT Osteoporosis:
  •        Calcium OR vitamin D is ok
  •        Calcium + vitamin D is good
  •        Calcium + vitamin D + other co-factors is great
  •        Low-cost Vitamin D Receptor activators sometimes may be helpful
  • CONCLUSION: To PREVENT many diseases, including Osteoporosis, as well as TREAT Osteoporosis
  • Category Osteoporosis has 218 items
  • Category Bone Health has 311 items

Note: Osteoporosis causes bones to become fragile and prone to fracture
  Osteoarthritis is a disease where damage occurs to the joints at the end of the bones

VitaminDWiki - Osteoporosis category includes

VitaminDWiki - Smoking reduces vitamin D - many studies contains

Two pathways are often proposed for how smoking decreases vitamin D:
   1) Smoking decreases Calcium. and Vitamin D is used up in replacing the Calcium
   2) Smoking injures the body, and vitamin D is used up in repairing the body
It appears that taking Vitamin D while smoking will:
   1) Decrease the incidence of the many health problems associated with smoking - even lung cancer
   2) Decrease the desire to smoke (perhaps take fewer smoking breaks?)
   3) Increase breathing capacity
Opinion: If you must smoke, have recently smoked, or are getting 2nd hand smoke:
   take Vitamin D and perhaps Omega-3
    They will extinguish much of the inflammation caused by inhaling tobacco smoke.
Vitamin D should also help people quit smoking   See bottom of page Smoking reduces vitamin D - many studies
   1) Reduces weight gain associated with quitting smoking
   2) Reduces depression associated with quitting smoking

VitaminDWiki - High Risk of low Vitamin D category

67 items in High Risk Category

Those at high-risk of being Vitamin D deficient will require about 1.5X more vitamin D to restore their levels
Those who are at risk due to being obese need about 2X more vitamin D to restore their levels

see also
  Overview Dark Skin
  Overview Seniors
  Overview Obesity
  Overview Pregnancy
  Overview Deficiency
   Shut-in category which has 39 items
   Middle East category which has 153 items

22 VitaminDWiki pages had CLOTH in the title as of July 2022
16+ VitaminDWiki pages with SHIFTWORK etc in the title
10 Groups Are More Prone To Vitamin D Deficiency - 2017 - additions include: >age 55, IBD, Vegans, Depression, Headaches

Viruses such as COVID and EBV deactivate the Vitamin D Receptor - which reduces the Vitamin D getting to cells


6410 visitors, last modified 14 Mar, 2022,
Printer Friendly Follow this page for updates