The causal relationship between sarcopenia and knee osteoarthritis: a Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

WU Hongfei ¹ , CUI Yushi ¹ ,  GAO Yun ¹ , ZHANG Xingping ² , ZHANG Shuai ¹ , WANG Mingyuan ¹ , YANG Shengping ¹ , ZHANG Zhilong ³

1. Eye Hospital, China Academy of Chinese Medical Sciences Beijing 100040, P. R. China;
2. Traditional Chinese Medicine Data Center, China Academy of Chinese Medical Sciences, Beijing 100193, P. R. China;
3. Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P. R. China;

Corresponding author：

GAO Yun, Email: gaoyun70@126.com

Keywords：

Mendelian randomization; Sarcopenia; Knee osteoarthritis; Causal inference

DOI：

10.7507/1672-2531.202411093

Video：

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Objective To conduct a Mendelian randomization (MR) analysis to elucidate the potential causal relationship between sarcopenia (SA) and knee osteoarthritis (KOA). Methods Three SA-related traits were selected as exposure factors from the summary data of the genome-wide association studies database (IEU GWAS). KOA and hospital-diagnosed osteoarthritis of the knee (osteoarthritis of the knee hospital diagnosed) were chosen as outcome factors. The inverse variance-weighted (IVW) method was employed as the primary analytical approach to evaluate the causal relationship between SA and KOA. Heterogeneity tests, sensitivity analyses, and pleiotropy analyses were conducted to validate the reliability of the results. Results The MR results indicated a substantial causal relationship between genetically predicted appendicular muscle mass(OR=1.079, 95%CI 1.015 to 1.147, P=0.015 5), walking speed(OR=0.157, 95%CI 0.101 to 0.248, P<0.001). No significant causal relationship was found between grip strength and KOA (OR=1.318, 95%CI 0.933 to 1.859, P=0.116 6), and the sensitivity analysis results did not exhibit horizontal pleiotropy. Conclusion SA may have a causal relationship with KOA, and appendicular muscle mass and walking speed may be risk factors for the occurrence and development of KOA.

1.	全国中医标准化技术委员会(SAC/TC 478). 中医临床名词术语第5部分: 骨伤科学: GB/T 42467.5-2023. 中国标准出版社, 2023: 12.
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3.	Liu CY, Duan YS, Zhou H, et al. Clinical effect and contributing factors of acupuncture for knee osteoarthritis: a systematic review and pairwise and exploratory network meta-analysis. BMJ Evid Based Med, 2024, 29(6): 374-384.
4.	Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis, 2014, 73(7): 1323-1330.
5.	吴红飞. KOA不同证候患者关节液TAOC、LPO浓度特点及其与证候程度相关性研究. 北京: 北京中医药大学, 2023.
6.	Yamagata M, Kimura T, Chang AH, et al. Sex Differences in ambulatory biomechanics: a meta-analysis providing a mechanistic insight into knee osteoarthritis. Med Sci Sports Exerc, 2025, 57(1): 144-153.
7.	Shahid A, Thirumaran AJ, Christensen R, et al. Comparison of weight loss interventions in overweight and obese adults with knee osteoarthritis: a systematic review and network meta-analysis of randomized trials. Osteoarthritis Cartilage, 2025, 33(4): 518-529.
8.	Weng SE, Huang YW, Tseng YC, et al. The evolving landscape of sarcopenia in Asia: a systematic review and meta-analysis following the 2019 Asian Working Group for Sarcopenia (AWGS) diagnostic criteria. Arch Gerontol Geriatr, 2025, 128: 105596.
9.	张姗姗, 刘航宇, 崔立敏, 等. 脆性骨折患者肌少症患病率及影响因素系统评价. 中华骨质疏松和骨矿盐疾病杂志, 2022, 15(4): 370-377.
10.	Sekula P, Del Greco MF, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
11.	Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
12.	彭洪俊, 曾羿. 肌肉减少症和骨关节炎相关性研究进展. 中国修复重建外科杂志, 2022, 36(12): 1549-1557.
13.	刘明, 高亚, 杨珂璐, 等. 孟德尔随机化研究的报告规范(STROBE-MR)解读. 中国循证医学杂志, 2022, 22(8): 978-987.
14.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
15.	Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing, 2019, 48(1): 16-31.
16.	徐婷, 袁名扬, 侯德仁. 多发性硬化与炎症性肠病的因果关联: 一项两样本双向孟德尔随机化研究. 中国循证医学杂志, 2024, 24(8): 893-898.
17.	Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol, 2013, 178(7): 1177-1184.
18.	Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
19.	Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ, 2021, 375: n2233.
20.	Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
21.	Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA, 2021, 326(16): 1614-1621.
22.	Yang W, Yang Y, He L, et al. Dietary factors and risk for asthma: a Mendelian randomization analysis. Front Immunol, 2023, 14: 1126457.
23.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
24.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
25.	Yan L, Ge H, Wang Z, et al. Roles of low muscle strength and sarcopenic obesity on incident symptomatic knee osteoarthritis: a longitudinal cohort study. PLoS One, 2024, 19(10): e0311423.
26.	Wu Q, Xu Z, Ma X, et al. Association of low muscle mass index and sarcopenic obesity with knee osteoarthritis: a systematic review and meta-analysis. J Int Soc Sports Nutr, 2024, 21(1): 2352393.
27.	Veronese N, Stefanac S, Koyanagi A, et al. Lower limb muscle strength and muscle mass are associated with incident symptomatic knee osteoarthritis: a longitudinal cohort study. Front Endocrinol (Lausanne), 2021, 12: 804560.
28.	Jin WS, Choi EJ, Lee SY, et al. Relationships among obesity, sarcopenia, and osteoarthritis in the elderly. J Obes Metab Syndr, 2017, 26(1): 36-44.
29.	Øiestad BE, Juhl CB, Culvenor AG, et al. Knee extensor muscle weakness is a risk factor for the development of knee osteoarthritis: an updated systematic review and meta-analysis including 46 819 men and women. Br J Sports Med, 2022, 56(6): 349-355.
30.	Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci, 2006, 61(10): 1059-1064.
31.	张丽, 瓮长水. 全身振动训练在老年康复领域应用的研究进展. 中国康复理论与实践, 2015, 21(2): 163-167.
32.	Kaji H. Effects of myokines on bone. Bonekey Rep, 2016, 5: 826.
33.	Kirk B, Feehan J, Lombardi G, et al. Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines. Curr Osteoporos Rep, 2020, 18(4): 388-400.
34.	He Z, Li H, Han X, et al. Irisin inhibits osteocyte apoptosis by activating the Erk signaling pathway in vitro and attenuates ALCT-induced osteoarthritis in mice. Bone, 2020, 141: 115573.
35.	Metzger CE, Anand Narayanan S, Phan PH, et al. Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment. NPJ Microgravity, 2020, 6: 28.
36.	Shang X, Hao X, Hou W, et al. Exercise-induced modulation of myokine irisin on muscle-bone unit in the rat model of post-traumatic osteoarthritis. J Orthop Surg Res, 2024, 19(1): 49.
37.	Habiballa L, Salmonowicz H, Passos JF. Mitochondria and cellular senescence: implications for musculoskeletal ageing. Free Radic Biol Med, 2019, 132: 3-10.
38.	Shen Y, Zhang Q, Huang Z, et al. Isoquercitrin delays denervated soleus muscle atrophy by inhibiting oxidative stress and inflammation. Front Physiol, 2020, 11: 988.
39.	Chen Z, Zhong H, Wei J, et al. Inhibition of Nrf2/HO-1 signaling leads to increased activation of the NLRP3 inflammasome in osteoarthritis. Arthritis Res Ther, 2019, 21(1): 300.
40.	Tchetverikov I, Lohmander LS, Verzijl N, et al. MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis. Ann Rheum Dis, 2005, 64(5): 694-698.
41.	Yu C, Xiao JH. The keap1-Nrf2 system: a mediator between oxidative stress and aging. Oxid Med Cell Longev, 2021, 2021: 6635460.
42.	Ahn B, Pharaoh G, Premkumar P, et al. Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass. Redox Biol, 2018, 17: 47-58.
43.	Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet, 2019, 393(10191): 2636-2646.
44.	Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing, 2019, 48(4): 601.
45.	Yuan S, Larsson SC. Epidemiology of sarcopenia: prevalence, risk factors, and consequences. Metabolism, 2023, 144: 155533.
46.	Liu C, Wong PY, Chung YL, et al. Deciphering the "obesity paradox" in the elderly: a systematic review and meta-analysis of sarcopenic obesity. Obes Rev, 2023, 24(2): e13534.

1. 全国中医标准化技术委员会(SAC/TC 478). 中医临床名词术语第5部分: 骨伤科学: GB/T 42467.5-2023. 中国标准出版社, 2023: 12.
2. 崔玉石, 吴红飞, 高云, 等. 由“髓减骨枯”与“微骨折”探讨骨质疏松症与膝骨关节炎的共病内涵. 中国骨质疏松杂志, 2024, 30(3): 391-395.
3. Liu CY, Duan YS, Zhou H, et al. Clinical effect and contributing factors of acupuncture for knee osteoarthritis: a systematic review and pairwise and exploratory network meta-analysis. BMJ Evid Based Med, 2024, 29(6): 374-384.
4. Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis, 2014, 73(7): 1323-1330.
5. 吴红飞. KOA不同证候患者关节液TAOC、LPO浓度特点及其与证候程度相关性研究. 北京: 北京中医药大学, 2023.
6. Yamagata M, Kimura T, Chang AH, et al. Sex Differences in ambulatory biomechanics: a meta-analysis providing a mechanistic insight into knee osteoarthritis. Med Sci Sports Exerc, 2025, 57(1): 144-153.
7. Shahid A, Thirumaran AJ, Christensen R, et al. Comparison of weight loss interventions in overweight and obese adults with knee osteoarthritis: a systematic review and network meta-analysis of randomized trials. Osteoarthritis Cartilage, 2025, 33(4): 518-529.
8. Weng SE, Huang YW, Tseng YC, et al. The evolving landscape of sarcopenia in Asia: a systematic review and meta-analysis following the 2019 Asian Working Group for Sarcopenia (AWGS) diagnostic criteria. Arch Gerontol Geriatr, 2025, 128: 105596.
9. 张姗姗, 刘航宇, 崔立敏, 等. 脆性骨折患者肌少症患病率及影响因素系统评价. 中华骨质疏松和骨矿盐疾病杂志, 2022, 15(4): 370-377.
10. Sekula P, Del Greco MF, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
11. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
12. 彭洪俊, 曾羿. 肌肉减少症和骨关节炎相关性研究进展. 中国修复重建外科杂志, 2022, 36(12): 1549-1557.
13. 刘明, 高亚, 杨珂璐, 等. 孟德尔随机化研究的报告规范(STROBE-MR)解读. 中国循证医学杂志, 2022, 22(8): 978-987.
14. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
15. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing, 2019, 48(1): 16-31.
16. 徐婷, 袁名扬, 侯德仁. 多发性硬化与炎症性肠病的因果关联: 一项两样本双向孟德尔随机化研究. 中国循证医学杂志, 2024, 24(8): 893-898.
17. Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol, 2013, 178(7): 1177-1184.
18. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
19. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ, 2021, 375: n2233.
20. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
21. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA, 2021, 326(16): 1614-1621.
22. Yang W, Yang Y, He L, et al. Dietary factors and risk for asthma: a Mendelian randomization analysis. Front Immunol, 2023, 14: 1126457.
23. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
24. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
25. Yan L, Ge H, Wang Z, et al. Roles of low muscle strength and sarcopenic obesity on incident symptomatic knee osteoarthritis: a longitudinal cohort study. PLoS One, 2024, 19(10): e0311423.
26. Wu Q, Xu Z, Ma X, et al. Association of low muscle mass index and sarcopenic obesity with knee osteoarthritis: a systematic review and meta-analysis. J Int Soc Sports Nutr, 2024, 21(1): 2352393.
27. Veronese N, Stefanac S, Koyanagi A, et al. Lower limb muscle strength and muscle mass are associated with incident symptomatic knee osteoarthritis: a longitudinal cohort study. Front Endocrinol (Lausanne), 2021, 12: 804560.
28. Jin WS, Choi EJ, Lee SY, et al. Relationships among obesity, sarcopenia, and osteoarthritis in the elderly. J Obes Metab Syndr, 2017, 26(1): 36-44.
29. Øiestad BE, Juhl CB, Culvenor AG, et al. Knee extensor muscle weakness is a risk factor for the development of knee osteoarthritis: an updated systematic review and meta-analysis including 46 819 men and women. Br J Sports Med, 2022, 56(6): 349-355.
30. Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci, 2006, 61(10): 1059-1064.
31. 张丽, 瓮长水. 全身振动训练在老年康复领域应用的研究进展. 中国康复理论与实践, 2015, 21(2): 163-167.
32. Kaji H. Effects of myokines on bone. Bonekey Rep, 2016, 5: 826.
33. Kirk B, Feehan J, Lombardi G, et al. Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines. Curr Osteoporos Rep, 2020, 18(4): 388-400.
34. He Z, Li H, Han X, et al. Irisin inhibits osteocyte apoptosis by activating the Erk signaling pathway in vitro and attenuates ALCT-induced osteoarthritis in mice. Bone, 2020, 141: 115573.
35. Metzger CE, Anand Narayanan S, Phan PH, et al. Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment. NPJ Microgravity, 2020, 6: 28.
36. Shang X, Hao X, Hou W, et al. Exercise-induced modulation of myokine irisin on muscle-bone unit in the rat model of post-traumatic osteoarthritis. J Orthop Surg Res, 2024, 19(1): 49.
37. Habiballa L, Salmonowicz H, Passos JF. Mitochondria and cellular senescence: implications for musculoskeletal ageing. Free Radic Biol Med, 2019, 132: 3-10.
38. Shen Y, Zhang Q, Huang Z, et al. Isoquercitrin delays denervated soleus muscle atrophy by inhibiting oxidative stress and inflammation. Front Physiol, 2020, 11: 988.
39. Chen Z, Zhong H, Wei J, et al. Inhibition of Nrf2/HO-1 signaling leads to increased activation of the NLRP3 inflammasome in osteoarthritis. Arthritis Res Ther, 2019, 21(1): 300.
40. Tchetverikov I, Lohmander LS, Verzijl N, et al. MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis. Ann Rheum Dis, 2005, 64(5): 694-698.
41. Yu C, Xiao JH. The keap1-Nrf2 system: a mediator between oxidative stress and aging. Oxid Med Cell Longev, 2021, 2021: 6635460.
42. Ahn B, Pharaoh G, Premkumar P, et al. Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass. Redox Biol, 2018, 17: 47-58.
43. Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet, 2019, 393(10191): 2636-2646.
44. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing, 2019, 48(4): 601.
45. Yuan S, Larsson SC. Epidemiology of sarcopenia: prevalence, risk factors, and consequences. Metabolism, 2023, 144: 155533.
46. Liu C, Wong PY, Chung YL, et al. Deciphering the "obesity paradox" in the elderly: a systematic review and meta-analysis of sarcopenic obesity. Obes Rev, 2023, 24(2): e13534.

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