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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2024

Open Access 01-12-2024 | Osteoporosis | Research

Diabetes and osteoporosis: a two-sample mendelian randomization study

Authors: Yu-Dun Qu, Zhao-Hua Zhu, Jia-Xuan Li, Wei Zhang, Qi Chen, Chang-Liang Xia, Jun-Nan Ma, Shuan-Ji Ou, Yang Yang, Yong Qi, Chang-Peng Xu

Published in: BMC Musculoskeletal Disorders | Issue 1/2024

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Abstract

Background

The effects on bone mineral density (BMD)/fracture between type 1 (T1D) and type 2 (T2D) diabetes are unknown. Therefore, we aimed to investigate the causal relationship between the two types of diabetes and BMD/fracture using a Mendelian randomization (MR) design.

Methods

A two-sample MR study was conducted to examine the causal relationship between diabetes and BMD/fracture, with three phenotypes (T1D, T2D, and glycosylated hemoglobin [HbA1c]) of diabetes as exposures and five phenotypes (femoral neck BMD [FN-BMD], lumbar spine BMD [LS-BMD], heel-BMD, total body BMD [TB-BMD], and fracture) as outcomes, combining MR-Egger, weighted median, simple mode, and inverse variance weighted (IVW) sensitivity assessments. Additionally, horizontal pleiotropy was evaluated and corrected using the residual sum and outlier approaches.

Results

The IVW method showed that genetically predicted T1D was negatively associated with TB-BMD (β = -0.018, 95% CI: -0.030, -0.006), while T2D was positively associated with FN-BMD (β = 0.033, 95% CI: 0.003, 0.062), heel-BMD (β = 0.018, 95% CI: 0.006, 0.031), and TB-BMD (β = 0.050, 95% CI: 0.022, 0.079). Further, HbA1c was not associated with the five outcomes (β ranged from − 0.012 to 0.075).

Conclusions

Our results showed that T1D and T2D have different effects on BMD at the genetic level. BMD decreased in patients with T1D and increased in those with T2D. These findings highlight the complex interplay between diabetes and bone health, suggesting potential age-specific effects and genetic influences. To better understand the mechanisms of bone metabolism in patients with diabetes, further longitudinal studies are required to explain BMD changes in different types of diabetes.
Appendix
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Literature
1.
Global regional. National disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of Disease Study 2017. Lancet (London England). 2018;392(10159):1859–922.CrossRef
2.
Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81.PubMedCrossRef
3.
van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011;91(1):79–118.PubMedCrossRef
4.
Khosla S, Samakkarnthai P, Monroe DG, Farr JN. Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus. Nat Reviews Endocrinol. 2021;17(11):685–97.CrossRef
5.
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO multinational study of Vascular Disease in Diabetes. Diabetologia. 2001;44(Suppl 2):S14–21.PubMedCrossRef
6.
Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE, Makaroff LE. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50.PubMedCrossRef
7.
8.
Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J, Burckhardt P, Cooper C, Christiansen C, Cummings S, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2007;18(8):1033–46.CrossRef
9.
Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2006;17(12):1726–33.CrossRef
10.
Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006;194(2 Suppl):S3–11.PubMedCrossRef
11.
Salari N, Ghasemi H, Mohammadi L, Behzadi MH, Rabieenia E, Shohaimi S, Mohammadi M. The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16(1):609.PubMedPubMedCentralCrossRef
12.
Abdulameer SA, Sulaiman SA, Hassali MA, Subramaniam K, Sahib MN. Osteoporosis and type 2 diabetes mellitus: what do we know, and what we can do? Patient Prefer Adherence. 2012;6:435–48.PubMedPubMedCentralCrossRef
13.
Gunczler P, Lanes R, Paoli M, Martinis R, Villaroel O, Weisinger JR. Decreased bone mineral density and bone formation markers shortly after diagnosis of clinical type 1 diabetes mellitus. J Pediatr Endocrinol Metabolism: JPEM. 2001;14(5):525–8.CrossRef
14.
Rehling T, Bjørkman AD, Andersen MB, Ekholm O, Molsted S. Diabetes Is Associated with Musculoskeletal Pain, Osteoarthritis, Osteoporosis, and Rheumatoid Arthritis. Journal of diabetes research 2019, 2019:6324348.
15.
Rakic V, Davis WA, Chubb SA, Islam FM, Prince RL, Davis TM. Bone mineral density and its determinants in diabetes: the Fremantle Diabetes Study. Diabetologia. 2006;49(5):863–71.PubMedCrossRef
16.
Botushanov NP, Orbetzova MM. Bone mineral density and fracture risk in patients with type 1 and type 2 diabetes mellitus. Folia Medica. 2009;51(4):12–7.PubMed
17.
Olmos JM, Pérez-Castrillón JL, García MT, Garrido JC, Amado JA, González-Macías J. Bone densitometry and biochemical bone remodeling markers in type 1 diabetes mellitus. Bone Miner. 1994;26(1):1–8.PubMedCrossRef
18.
Nicodemus KK, Folsom AR. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care. 2001;24(7):1192–7.PubMedCrossRef
19.
Forsén L, Meyer HE, Midthjell K, Edna TH. Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trøndelag Health Survey. Diabetologia. 1999;42(8):920–5.PubMedCrossRef
20.
Heath H 3rd, Melton LJ 3rd, Chu CP. Diabetes mellitus and risk of skeletal fracture. N Engl J Med. 1980;303(10):567–70.PubMedCrossRef
21.
Melchior TM, Sørensen H, Torp-Pedersen C. Hip and distal arm fracture rates in peri- and postmenopausal insulin-treated diabetic females. J Intern Med. 1994;236(2):203–8.PubMedCrossRef
22.
Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89–98.PubMedPubMedCentralCrossRef
23.
Fan J, Zhu J, Sun L, Li Y, Wang T, Li Y. Causal association of adipokines with osteoarthritis: a mendelian randomization study. Rheumatology (Oxford). 2021;60(6):2808–15.PubMedCrossRef
24.
ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, et al. 2. Classification and diagnosis of diabetes: standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S19–40.PubMedCrossRef
25.
Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, Rosas SE, Del Prato S, Mathieu C, Mingrone G, et al. Management of hyperglycemia in type 2 diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753–86.PubMedPubMedCentralCrossRef
26.
Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, VanderWeele TJ, Higgins JPT, Timpson NJ, Dimou N, et al. Strengthening the reporting of Observational studies in Epidemiology using mendelian randomization: the STROBE-MR Statement. JAMA. 2021;326(16):1614–21.PubMedCrossRef
27.
Censin JC, Nowak C, Cooper N, Bergsten P, Todd JA, Fall T. Childhood adiposity and risk of type 1 diabetes: a mendelian randomization study. PLoS Med. 2017;14(8):e1002362.PubMedPubMedCentralCrossRef
28.
Zhao W, Rasheed A, Tikkanen E, Lee JJ, Butterworth AS, Howson JMM, Assimes TL, Chowdhury R, Orho-Melander M, Damrauer S, et al. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet. 2017;49(10):1450–7.PubMedPubMedCentralCrossRef
29.
Soranzo N, Sanna S, Wheeler E, Gieger C, Radke D, Dupuis J, Bouatia-Naji N, Langenberg C, Prokopenko I, Stolerman E, et al. Common variants at 10 genomic loci influence hemoglobin A1(C) levels via glycemic and nonglycemic pathways. Diabetes. 2010;59(12):3229–39.PubMedPubMedCentralCrossRef
30.
Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OM, Amin N, Kemp JP, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44(5):491–501.PubMedPubMedCentralCrossRef
31.
Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS, Mook-Kanamori DO, Ham A, Hartwig FP, Evans DS, et al. Life-Course Genome-Wide Association Study Meta-Analysis of Total Body BMD and Assessment of Age-Specific effects. Am J Hum Genet. 2018;102(1):88–102.PubMedPubMedCentralCrossRef
32.
Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, Vulpescu NA, Forgetta V, Kleinman A, Mohanty ST, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019;51(2):258–66.PubMedCrossRef
33.
Wang Y, Li T, Fu L, Yang S, Hu YQ. A Novel Method for mendelian randomization analyses with pleiotropy and linkage disequilibrium in genetic variants from Individual Data. Front Genet. 2021;12:634394.PubMedPubMedCentralCrossRef
34.
Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas P, Eisman JA, Fujiwara S, Kroger H, Mellstrom D, et al. Predictive value of BMD for hip and other fractures. J bone Mineral Research: Official J Am Soc Bone Mineral Res. 2005;20(7):1185–94.CrossRef
35.
Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526(7571):112–7.PubMedPubMedCentralCrossRef
36.
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some Invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14.PubMedPubMedCentralCrossRef
37.
Arnold M, Raffler J, Pfeufer A, Suhre K, Kastenmüller G. SNiPA: an interactive, genetic variant-centered annotation browser. Bioinf (Oxford England). 2015;31(8):1334–6.
38.
Lanzinger S, Zimmermann A, Ranjan AG, Gani O, Pons Perez S, Akesson K, Majidi S, Witsch M, Hofer S, Johnson S et al. A collaborative comparison of international pediatric diabetes registries. Pediatric diabetes 2022.
39.
Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J bone Mineral Research: Official J Am Soc Bone Mineral Res. 2011;26(8):1729–39.CrossRef
40.
Chen SC, Shepherd S, McMillan M, McNeilly J, Foster J, Wong SC, Robertson KJ, Ahmed SF. Skeletal fragility and its clinical determinants in children with type 1 diabetes. J Clin Endocrinol Metab. 2019;104(8):3585–94.PubMedCrossRef
41.
Syversen U, Mosti MP, Mynarek IM, Vedal TSJ, Aasarød K, Basso T, Reseland JE, Thorsby PM, Asvold BO, Eriksen EF, et al. Evidence of impaired bone quality in men with type 1 diabetes: a cross-sectional study. Endocr Connections. 2021;10(8):955–64.CrossRef
42.
Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL. Mechanisms of diabetes mellitus-induced bone fragility. Nat Reviews Endocrinol. 2017;13(4):208–19.CrossRef
43.
Tang Y, Zhang L, Ye D, Zhao A, Liu Y, Zhang M. Causal relationship between type 1 diabetes and osteoporosis and fracture occurrence: a two-sample mendelian randomization analysis. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2023;34(6):1111–7.CrossRef
44.
45.
McComb C, Harpur A, Yacoubian C, Leddy C, Anderson G, Shepherd S, Perry C, Shaikh MG, Foster J, Ahmed SF. MRI-based abnormalities in young adults at risk of adverse bone health due to childhood-onset metabolic & endocrine conditions. Clin Endocrinol. 2014;80(6):811–7.CrossRef
46.
Cheng L, Wang S, Tang H. Type 2 diabetes mellitus plays a protective role against osteoporosis --mendelian randomization analysis. BMC Musculoskelet Disord. 2023;24(1):444.PubMedPubMedCentralCrossRef
47.
Ahmad OS, Leong A, Miller JA, Morris JA, Forgetta V, Mujammami M, Richards JB. A mendelian randomization study of the effect of Type-2 diabetes and glycemic traits on bone Mineral Density. J bone Mineral Research: Official J Am Soc Bone Mineral Res. 2017;32(5):1072–81.CrossRef
48.
Kindler JM, Gallo S, Khoury PR, Urbina EM, Zemel BS. Diet Quality and Bone Density in Youth with Healthy Weight, obesity, and type 2 diabetes. Nutrients 2021, 13(9).
49.
de Klift LII, de Laet M, van Daele CE, Hofman PL, Pols A. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2005;16(12):1713–20.CrossRef
50.
Gatling W, Guzder RN, Turnbull JC, Budd S, Mullee MA. The Poole Diabetes Study: how many cases of type 2 diabetes are diagnosed each year during normal health care in a defined community? Diabetes Res Clin Pract. 2001;53(2):107–12.PubMedCrossRef
51.
52.
Thrailkill KM, Lumpkin CK Jr., Bunn RC, Kemp SF, Fowlkes JL. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metabolism. 2005;289(5):E735–745.CrossRef
53.
Hamann C, Kirschner S, Günther KP, Hofbauer LC. Bone, sweet bone–osteoporotic fractures in diabetes mellitus. Nat Reviews Endocrinol. 2012;8(5):297–305.CrossRef
54.
Patsch JM, Burghardt AJ, Yap SP, Baum T, Schwartz AV, Joseph GB, Link TM. Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J bone Mineral Research: Official J Am Soc Bone Mineral Res. 2013;28(2):313–24.CrossRef
55.
Botella Martínez S, Varo Cenarruzabeitia N, Escalada San Martin J, Calleja Canelas A. The diabetic paradox: bone mineral density and fracture in type 2 diabetes. Endocrinologia Y Nutricion: organo de la Sociedad Esp De Endocrinologia Y Nutricion. 2016;63(9):495–501.CrossRef
56.
Li G, Prior JC, Leslie WD, Thabane L, Papaioannou A, Josse RG, Kaiser SM, Kovacs CS, Anastassiades T, Towheed T, et al. Frailty and Risk of fractures in patients with type 2 diabetes. Diabetes Care. 2019;42(4):507–13.PubMedCrossRef
57.
Kennedy CC, Ioannidis G, Rockwood K, Thabane L, Adachi JD, Kirkland S, Pickard LE, Papaioannou A. A Frailty Index predicts 10-year fracture risk in adults age 25 years and older: results from the Canadian Multicentre osteoporosis study (CaMos). Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2014;25(12):2825–32.CrossRef
58.
Joad S, Ballato E, Deepika F, Gregori G, Fleires-Gutierrez AL, Colleluori G, Aguirre L, Chen R, Russo V, Fuenmayor Lopez VC, et al. Hemoglobin A1c threshold for reduction in bone turnover in men with type 2 diabetes Mellitus. Front Endocrinol. 2021;12:788107.CrossRef
59.
Thong EP, Herath M, Weber DR, Ranasinha S, Ebeling PR, Milat F, Teede H. Fracture risk in young and middle-aged adults with type 1 diabetes mellitus: a systematic review and meta-analysis. Clin Endocrinol. 2018;89(3):314–23.CrossRef
60.
Dytfeld J, Michalak M. Type 2 diabetes and risk of low-energy fractures in postmenopausal women: meta-analysis of observational studies. Aging Clin Exp Res. 2017;29(2):301–9.PubMedCrossRef
61.
Fan Y, Wei F, Lang Y, Liu Y. Diabetes mellitus and risk of hip fractures: a meta-analysis. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2016;27(1):219–28.CrossRef
62.
Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes–a meta-analysis. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2007;18(4):427–44.CrossRef
63.
De Laet C, Kanis JA, Odén A, Johanson H, Johnell O, Delmas P, Eisman JA, Kroger H, Fujiwara S, Garnero P, et al. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2005;16(11):1330–8.CrossRef
64.
Palermo A, D’Onofrio L, Eastell R, Schwartz AV, Pozzilli P, Napoli N. Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos International: J Established as Result Cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2015;26(8):2073–89.CrossRef
65.
de Jong VM, van der Slik AR, Laban S, van ‘t Slot R, Koeleman BP, Zaldumbide A, Roep BO. Survival of autoreactive T lymphocytes by microRNA-mediated regulation of apoptosis through TRAIL and Fas in type 1 diabetes. Genes Immun. 2016;17(6):342–8.PubMedCrossRef
66.
67.
Prudente S, Trischitta V. Editorial: the pleiotropic effect of the ENPP1 (PC-1) gene on insulin resistance, obesity, and type 2 diabetes. J Clin Endocrinol Metab. 2006;91(12):4767–8.PubMedCrossRef
Metadata
Title
Diabetes and osteoporosis: a two-sample mendelian randomization study
Authors
Yu-Dun Qu
Zhao-Hua Zhu
Jia-Xuan Li
Wei Zhang
Qi Chen
Chang-Liang Xia
Jun-Nan Ma
Shuan-Ji Ou
Yang Yang
Yong Qi
Chang-Peng Xu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2024
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-024-07430-0

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