Telomere length as a predictive biomarker in osteoporosis (Review)

Kakridonis,Fotios; Pneumatikos,Spyros G.; Vakonaki,Elena; Berdiaki,Aikaterini; Tzatzarakis,Manolis N.; Fragkiadaki,Persefoni; Spandidos,Demetrios A.; Baliou,Stella; Ioannou,Petros; Hatzidaki,Eleftheria; Nikitovic,Dragana; Tsatsakis,Aristidis; Vasiliadis,Elias

doi:10.3892/br.2023.1669

Telomere length as a predictive biomarker in osteoporosis (Review)

Authors:
- Fotios Kakridonis
- Spyros G. Pneumatikos
- Elena Vakonaki
- Aikaterini Berdiaki
- Manolis N. Tzatzarakis
- Persefoni Fragkiadaki
- Demetrios A. Spandidos
- Stella Baliou
- Petros Ioannou
- Eleftheria Hatzidaki
- Dragana Nikitovic
- Aristidis Tsatsakis
- Elias Vasiliadis
View Affiliations

Affiliations: 5th Department of Orthopaedics, KAT Attica General Hospital, 14561 Athens, Greece, 3rd Department of Orthopaedics, KAT Attica General Hospital, 14561 Athens, Greece, Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece, Laboratory of Anatomy‑Histology‑Embryology, Medical School, University of Crete, 71003 Heraklion, Greece, Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece, Laboratory of Internal Medicine, Medical School, University of Crete, 71003 Heraklion, Greece, Department of Neonatology and NICU, University Hospital of Heraklion, 71500 Heraklion, Greece
Published online on: October 3, 2023 https://doi.org/10.3892/br.2023.1669
Article Number: 87
Copyright: © Kakridonis et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Telomeres are the ends of chromosomes that protect them from DNA damage. There is evidence to suggest that telomere shortening appears with advanced age. Since aging is a significant risk factor for developing age‑related complications, it is plausible that telomere shortening may be involved in the development of osteoporosis. The present review summarizes the potential of telomere shortening as a biomarker for detecting the onset of osteoporosis. For the purposes of the present review, the following scientific databases were searched for relevant articles: PubMed/NCBI, Cochrane Library of Systematic Reviews, Scopus, Embase and Google Scholar. The present review includes randomized and non‑randomized controlled studies and case series involving humans, irrespective of the time of their publication. In six out of the 11 included studies providing data on humans, there was at least a weak association between telomere length and osteoporosis, with the remaining studies exhibiting no such association. As a result, telomere shortening may be used as a biomarker or as part of a panel of biomarkers for tracking the onset and progression of osteoporosis.

View Figures

View References

1	Shay JW: Telomeres and aging. Curr Opin Cell Biol. 52:1–7. 2018.PubMed/NCBI View Article : Google Scholar
2	Gruber HJ, Semeraro MD, Renner W and Herrmann M: Telomeres and Age-Related Diseases. Biomedicines. 9(1335)2021.PubMed/NCBI View Article : Google Scholar
3	Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H and de Lange T: Mammalian Telomeres End in a Large Duplex Loop. Cell. 97:503–514. 1999.PubMed/NCBI View Article : Google Scholar
4	Greider CW: Telomeres Do D-Loop-T-Loop. Cell. 97:419–422. 1999.PubMed/NCBI View Article : Google Scholar
5	Turner KJ, Vasu V and Griffin DK: Telomere biology and human phenotype. Cells. 8(73)2019.PubMed/NCBI View Article : Google Scholar
6	de Lange T: Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev. 19:2100–2110. 2005.PubMed/NCBI View Article : Google Scholar
7	Blasco MA: Telomere length, stem cells and aging. Nat Chem Biol. 3:640–649. 2007.PubMed/NCBI View Article : Google Scholar
8	Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadiñanos J, et al: Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 469:102–106. 2011.PubMed/NCBI View Article : Google Scholar
9	Tsoukalas D, Fragkiadaki P, Docea AO, Alegakis AK, Sarandi E, Vakonaki E, Salataj E, Kouvidi E, Nikitovic D, Kovatsi L, et al: Association of nutraceutical supplements with longer telomere length. Int J Mol Med. 44:218–226. 2019.PubMed/NCBI View Article : Google Scholar
10	Tsoukalas D, Buga AM, Docea AO, Sarandi E, Mitrut R, Renieri E, Spandidos DA, Rogoveanu I, Cercelaru L, Niculescu M, et al: Reversal of brain aging by targeting telomerase: A nutraceutical approach. Int J Mol Med. 48(199)2021.PubMed/NCBI View Article : Google Scholar
11	López-Otín C, Blasco MA, Partridge L, Serrano M and Kroemer G: The Hallmarks of Aging. Cell. 153:1194–1217. 2013.PubMed/NCBI View Article : Google Scholar
12	Lederman S: American Federation for Aging Research. In: Encyclopedia of Gerontology and Population Aging. Gu D and Dupre ME (eds). Springer, Cham, pp1–5, 2020.
13	Vaiserman A and Krasnienkov D: Telomere length as a marker of biological age: State-of-the-Art, open issues, and future perspectives. Front Genet. 11(630186)2021.PubMed/NCBI View Article : Google Scholar
14	Rossiello F, Jurk D, Passos JF and d'Adda di Fagagna F: Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol. 24:135–147. 2022.PubMed/NCBI View Article : Google Scholar
15	Sanders JL and Newman AB: Telomere length in epidemiology: A biomarker of aging, age-related disease, both, or neither? Epidemiol Rev. 35:112–131. 2013.PubMed/NCBI View Article : Google Scholar
16	Valdes AM, Richards JB, Gardner JP, Swaminathan R, Kimura M, Xiaobin L, Aviv A and Spector TD: Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos Int. 18:1203–1210. 2007.PubMed/NCBI View Article : Google Scholar
17	Farr JN and Khosla S: Cellular senescence in bone. Bone. 121:121–133. 2019.PubMed/NCBI View Article : Google Scholar
18	Sozen T, Ozisik L and Basaran NC: An overview and management of osteoporosis. Eur J Rheumatol. 4:46–56. 2017.PubMed/NCBI View Article : Google Scholar
19	Chen X, Hu Y, Geng Z and Su J: The ‘Three in One’ Bone repair strategy for osteoporotic fractures. Front Endocrinol (Lausanne). 13(910602)2022.PubMed/NCBI View Article : Google Scholar
20	Dimai HP, Redlich K, Peretz M, Borgström F, Siebert U and Mahlich J: Economic burden of osteoporotic fractures in Austria. Health Econ Rev. 2(12)2012.PubMed/NCBI View Article : Google Scholar
21	Johnston CB and Dagar M: Osteoporosis in older adults. Med Clin North Am. 104:873–884. 2020.PubMed/NCBI View Article : Google Scholar
22	Pignolo RJ, Law SF and Chandra A: Bone aging, cellular senescence, and osteoporosis. JBMR Plus. 5(e10488)2021.PubMed/NCBI View Article : Google Scholar
23	Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S and Dawson-Hughes B: 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. 29:2520–2526. 2014.PubMed/NCBI View Article : Google Scholar
24	Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, Kleerekoper M, Luckey MM, McClung MR, Pollack RP, et al: American association of clinical endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 16 Suppl 3(Suppl 3):S1–S37. 2010.PubMed/NCBI View Article : Google Scholar
25	Khosla S: Pathogenesis of Age-Related Bone Loss in Humans. J Gerontol A Biol Sci Med Sci. 68:1226–1235. 2013.PubMed/NCBI View Article : Google Scholar
26	Chandra A, Lagnado AB, Farr JN, Monroe DG, Park S, Hachfeld C, Tchkonia T, Kirkland JL, Khosla S, Passos JF and Pignolo RJ: Targeted reduction of senescent cell burden alleviates focal radiotherapy-related bone loss. J Bone Miner Res. 35:1119–1131. 2020.PubMed/NCBI View Article : Google Scholar
27	Chandra A and Rajawat J: Skeletal aging and osteoporosis: Mechanisms and Therapeutics. Int J Mol Sci. 22(3553)2021.PubMed/NCBI View Article : Google Scholar
28	Farr JN, Rowsey JL, Eckhardt BA, Thicke BS, Fraser DG, Tchkonia T, Kirkland JL, Monroe DG and Khosla S: Independent roles of estrogen deficiency and cellular senescence in the pathogenesis of osteoporosis: Evidence in young adult mice and older humans. J Bone Miner Res. 34:1407–1418. 2019.PubMed/NCBI View Article : Google Scholar
29	Hachemi Y, Rapp AE, Picke AK, Weidinger G, Ignatius A and Tuckermann J: Molecular mechanisms of glucocorticoids on skeleton and bone regeneration after fracture. J Mol Endocrinol. 61:R75–R90. 2018.PubMed/NCBI View Article : Google Scholar
30	Siddiqui JA and Partridge NC: Physiological bone remodeling: Systemic regulation and growth factor involvement. Physiology (Bethesda). 31:233–245. 2016.PubMed/NCBI View Article : Google Scholar
31	Kenkre JS and Bassett J: The bone remodelling cycle. Ann Clin Biochem. 55:308–327. 2018.PubMed/NCBI View Article : Google Scholar
32	Rauner M, Taipaleenmäki H, Tsourdi E and Winter EM: Osteoporosis treatment with anti-sclerostin antibodies-mechanisms of action and clinical application. J Clin Med. 10(787)2021.PubMed/NCBI View Article : Google Scholar
33	Fabre S, Funck-Brentano T and Cohen-Solal M: Anti-Sclerostin antibodies in osteoporosis and other bone diseases. J Clin Med. 9(3439)2020.PubMed/NCBI View Article : Google Scholar
34	Shakeri A and Adanty C: Romosozumab (sclerostin monoclonal antibody) for the treatment of osteoporosis in postmenopausal women: A review. J Popul Ther Clin Pharmacol. 27:e25–e31. 2020.PubMed/NCBI View Article : Google Scholar
35	Ensrud KE and Crandall CJ: Osteoporosis. Ann Intern Med. 167:ITC17–ITC32. 2017.PubMed/NCBI View Article : Google Scholar
36	Mather KA, Jorm AF, Parslow RA and Christensen H: Is telomere length a biomarker of aging? A review. J Gerontol A Biol Sci Med Sci. 66A:202–213. 2011.PubMed/NCBI View Article : Google Scholar
37	Der G, Batty GD, Benzeval M, Deary IJ, Green MJ, McGlynn L, McIntyre A, Robertson T and Shiels PG: Is telomere length a biomarker for aging: Cross-Sectional evidence from the west of scotland? PLoS One. 7(e45166)2012.PubMed/NCBI View Article : Google Scholar
38	Simons MJ: Questioning causal involvement of telomeres in aging. Ageing Res Rev. 24(Pt B):191–196. 2015.PubMed/NCBI View Article : Google Scholar
39	Gorenjak V, Akbar S, Stathopoulou MG and Visvikis-Siest S: The future of telomere length in personalized medicine. Front Biosci (Landmark Ed). 23:1628–1654. 2018.PubMed/NCBI View Article : Google Scholar
40	Fasching CL: Telomere length measurement as a clinical biomarker of aging and disease. Crit Rev Clin Lab Sci. 55:443–465. 2018.PubMed/NCBI View Article : Google Scholar
41	Bekaert S, Van Pottelbergh I, De Meyer T, Zmierczak H, Kaufman JM, Van Oostveldt P and Goemaere S: Telomere length versus hormonal and bone mineral status in healthy elderly men. Mech Ageing Dev. 126:1115–1122. 2005.PubMed/NCBI View Article : Google Scholar
42	Cawthon RM, Smith KR, O'Brien E, Sivatchenko A and Kerber RA: Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 361:393–395. 2003.PubMed/NCBI View Article : Google Scholar
43	Kassem M and Marie PJ: Senescence-associated intrinsic mechanisms of osteoblast dysfunctions: Age-related mechanisms of osteoblast dysfunctions. Aging Cell. 10:191–197. 2011.PubMed/NCBI View Article : Google Scholar
44	Wang D and Wang H: Cellular Senescence in Bone. In: Physiology. Heshmati H (ed). IntechOpen, vol. 15 M, 2022.
45	Tamayo M, Mosquera A, Rego JI, Fernández-Sueiro JL, Blanco FJ and Fernández JL: Differing patterns of peripheral blood leukocyte telomere length in rheumatologic diseases. Mutat Res. 683:68–73. 2010.PubMed/NCBI View Article : Google Scholar
46	Nielsen BR, Linneberg A, Bendix L, Harboe M, Christensen K and Schwarz P: Association between leukocyte telomere length and bone mineral density in women 25-93 years of age. Exp Gerontol. 66:25–31. 2015.PubMed/NCBI View Article : Google Scholar
47	Smith RL, de Boer R, Brul S, Budovskaya Y and van Spek H: Premature and accelerated aging: HIV or HAART? Front Genet. 3(328)2013.PubMed/NCBI View Article : Google Scholar
48	Deeks SG: HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 62:141–155. 2011.PubMed/NCBI View Article : Google Scholar
49	Kalyan S, Pick N, Mai A, Murray MCM, Kidson K, Chu J, Albert AYK, Côté HCF, Maan EJ, Goshtasebi A, et al: Premature spinal bone loss in women living with HIV is associated with shorter leukocyte telomere length. Int J Environ Res Public Health. 15(1018)2018.PubMed/NCBI View Article : Google Scholar
50	Brown TT and Qaqish RB: Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review. AIDS. 20:2165–2174. 2006.PubMed/NCBI View Article : Google Scholar
51	Tao L, Huang Q, Yang R, Dai Y, Zeng Y, Li C, Li X, Zeng J and Wang Q: The age modification to leukocyte telomere length effect on bone mineral density and osteoporosis among Chinese elderly women. J Bone Miner Metab. 37:1004–1012. 2019.PubMed/NCBI View Article : Google Scholar
52	Fragkiadaki P, Nikitovic D, Kalliantasi K, Sarandi E, Thanasoula M, Stivaktakis PD, Nepka C, Spandidos DA, Tosounidis T and Tsatsakis A: Telomere length and telomerase activity in osteoporosis and osteoarthritis. Exp Ther Med. 19:1626–1632. 2020.PubMed/NCBI View Article : Google Scholar
53	Curtis EM, Codd V, Nelson C, D'Angelo S, Wang Q, Allara E, Kaptoge S, Matthews PM, Tobias JH, Danesh J, et al: Telomere length and risk of incident fracture and arthroplasty: Findings from UK Biobank. J Bone Miner Res. 37:1997–2004. 2022.PubMed/NCBI View Article : Google Scholar
54	Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, Drake MT, Tchkonia T, LeBrasseur NK, Kirkland JL, et al: Identification of senescent cells in the bone microenvironment. J Bone Miner Res. 31:1920–1929. 2016.PubMed/NCBI View Article : Google Scholar
55	Haapanen MJ, Perälä MM, Salonen MK, Guzzardi MA, Iozzo P, Kajantie E, Rantanen T, Simonen M, Pohjolainen P, Eriksson JG and von Bonsdorff MB: Telomere length and frailty: The Helsinki birth cohort study. J Am Med Dir Assoc. 19:658–662. 2018.PubMed/NCBI View Article : Google Scholar
56	Hong Z, Lin X, Zhou Y, Zheng G, Liao X, Wei Q, Zhang Z and Liang J: Lean body mass but not body fat mass is related with leukocyte telomere length in children. Int J Obes (Lond). 47:67–74. 2023.PubMed/NCBI View Article : Google Scholar
57	Pignolo RJ, Suda RK, McMillan EA, Shen J, Lee SH, Choi Y, Wright AC and Johnson FB: Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. Aging Cell. 7:23–31. 2008.PubMed/NCBI View Article : Google Scholar
58	Brennan TA, Egan KP, Lindborg CM, Chen Q, Sweetwyne MT, Hankenson KD, Xie SX, Johnson FB and Pignolo RJ: Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis. Dis Model Mech. 7:583–592. 2014.PubMed/NCBI View Article : Google Scholar
59	Singh L, Brennan TA, Kim JH, Egan KP, McMillan EA, Chen Q, Hankenson KD, Zhang Y, Emerson SG, Johnson FB and Pignolo RJ: Long-Term functional engraftment of mesenchymal progenitor cells in a mouse model of accelerated aging. Stem Cells. 31:607–611. 2013.PubMed/NCBI View Article : Google Scholar
60	Kveiborg M, Kassem M, Langdahl B, Eriksen EF, Clark BF and Rattan SI: Telomere shortening during aging of human osteoblasts in vitro and leukocytes in vivo: Lack of excessive telomere loss in osteoporotic patients. Mech Ageing Dev. 106:261–271. 1999.PubMed/NCBI View Article : Google Scholar
61	Tang NL, Woo J, Suen EW, Liao CD, Leung JC and Leung PC: The effect of telomere length, a marker of biological aging, on bone mineral density in elderly population. Osteoporos Int. 21:89–97. 2010.PubMed/NCBI View Article : Google Scholar
62	Kirk B, Kuo CL, Xiang M and Duque G: Associations between leukocyte telomere length and osteosarcopenia in 20,400 adults aged 60 years and over: Data from the UK Biobank. Bone. 161(116425)2022.PubMed/NCBI View Article : Google Scholar
63	Sepúlveda-Loyola W, Phu S, Bani Hassan E, Brennan-Olsen SL, Zanker J, Vogrin S, Conzade R, Kirk B, Al Saedi A, Probst V and Duque G: The joint occurrence of osteoporosis and sarcopenia (Osteosarcopenia): Definitions and Characteristics. J Am Med Dir Assoc. 21:220–225. 2020.PubMed/NCBI View Article : Google Scholar
64	Aviv A, Valdes AM and Spector TD: Human telomere biology: Pitfalls of moving from the laboratory to epidemiology. Int J Epidemiol. 35:1424–1429. 2006.PubMed/NCBI View Article : Google Scholar
65	Sanders JL, Cauley JA, Boudreau RM, Zmuda JM, Strotmeyer ES, Opresko PL, Hsueh WC, Cawthon RM, Li R, Harris TB, et al: Leukocyte Telomere length is not associated with BMD, osteoporosis, or fracture in older adults: Results from the health, aging and body composition study. J Bone Miner Res. 24:1531–1536. 2009.PubMed/NCBI View Article : Google Scholar
66	Saeed H, Abdallah BM, Ditzel N, Catala-Lehnen P, Qiu W, Amling M and Kassem M: Telomerase-deficient mice exhibit bone loss owing to defects in osteoblasts and increased osteoclastogenesis by inflammatory microenvironment. J Bone Miner Res. 26:1494–1505. 2011.PubMed/NCBI View Article : Google Scholar
67	Baird D: New developments in telomere length analysis. Exp Gerontol. 40:363–368. 2005.PubMed/NCBI View Article : Google Scholar
68	Lai TP, Zhang N, Noh J, Mender I, Tedone E, Huang E, Wright WE, Danuser G and Shay JW: A method for measuring the distribution of the shortest telomeres in cells and tissues. Nat Commun. 8(1356)2017.PubMed/NCBI View Article : Google Scholar
69	Lu AT, Seeboth A, Tsai PC, Sun D, Quach A, Reiner AP, Kooperberg C, Ferrucci L, Hou L, Baccarelli AA, et al: DNA methylation-based estimator of telomere length. Aging (Albany NY). 11:5895–5923. 2019.PubMed/NCBI View Article : Google Scholar
70	Dagnall CL, Hicks B, Teshome K, Hutchinson AA, Gadalla SM, Khincha PP, Yeager M and Savage SA: Effect of pre-analytic variables on the reproducibility of qPCR relative telomere length measurement. PLoS One. 12(e0184098)2017.PubMed/NCBI View Article : Google Scholar
71	Lin J, Smith DL, Esteves K and Drury S: Telomere length measurement by qPCR-Summary of critical factors and recommendations for assay design. Psychoneuroendocrinology. 99:271–278. 2019.PubMed/NCBI View Article : Google Scholar
72	Bodelon C, Savage SA and Gadalla SM: Telomeres in Molecular Epidemiology Studies. Prog Mol Biol Transl Sci. 125:113–131. 2014.PubMed/NCBI View Article : Google Scholar
73	Semeraro MD, Smith C, Kaiser M, Levinger I, Duque G, Gruber HJ and Herrmann M: Physical activity, a modulator of aging through effects on telomere biology. Aging (Albany NY). 12:13803–13823. 2020.PubMed/NCBI View Article : Google Scholar
74	Kirwan M and Dokal I: Dyskeratosis congenita, stem cells and telomeres. Biochim Biophys Acta. 1792:371–379. 2009.PubMed/NCBI View Article : Google Scholar
75	McGrath JA: Dyskeratosis congenita: New clinical and molecular insights into ribosome function. Lancet. 353:1204–1205. 1999.PubMed/NCBI View Article : Google Scholar
76	Tsuge K and Shimamoto A: Research on werner syndrome: Trends from past to present and future prospects. Genes (Basel). 13(1802)2022.PubMed/NCBI View Article : Google Scholar
77	Du X, Shen J, Kugan N, Furth EE, Lombard DB, Cheung C, Pak S, Luo G, Pignolo RJ, DePinho RA, et al: Telomere shortening exposes functions for the mouse werner and bloom syndrome genes. Mol Cell Biol. 24:8437–8446. 2004.PubMed/NCBI View Article : Google Scholar
78	Hofer AC, Tran RT, Aziz OZ, Wright W, Novelli G, Shay J and Lewis M: Shared phenotypes among segmental progeroid syndromes suggest underlying pathways of aging. J Gerontol A Biol Sci Med Sci. 60:10–20. 2005.PubMed/NCBI View Article : Google Scholar
79	Mason PJ, Wilson DB and Bessler M: Dyskeratosis Congenita-A disease of dysfunctional telomere maintenance. Curr Mol Med. 5:159–170. 2005.PubMed/NCBI View Article : Google Scholar
80	Salminen A, Suuronen T, Huuskonen J and Kaarniranta K: NEMO shuttle: A link between DNA damage and NF-kappaB activation in progeroid syndromes? Biochem Biophys Res Commun. 367:715–718. 2008.PubMed/NCBI View Article : Google Scholar
81	Crabbe L, Verdun RE, Haggblom CI and Karlseder J: Defective telomere lagging strand synthesis in cells lacking WRN Helicase activity. Science. 306:1951–1953. 2004.PubMed/NCBI View Article : Google Scholar
82	Majors AK, Boehm CA, Nitto H, Midura RJ and Muschler GF: Characterization of human bone marrow stromal cells with respect to osteoblastic differentiation. J Orthop Res. 15:546–557. 1997.PubMed/NCBI View Article : Google Scholar