Biomedical Risk Factors of Achilles Tendinopathy in Physically Active People: a Systematic Review
Kozlovskaia et al. Sports Medicine - Open
Biomedical Risk Factors of Achilles Tendinopathy in Physically Active People: a Systematic Review
Maria Kozlovskaia 0 1
Nicole Vlahovich 0
Kevin J. Ashton 1
David C. Hughes 0
0 Department of Sports Medicine, Australian Institute of Sport , 1 Leverrier Street, Bruce, ACT 2617 , Australia
1 Faculty of Health Sciences and Medicine, Bond University , 14 University Drive, Robina, QLD 4226 , Australia
Background: Achilles tendinopathy is the most prevalent tendon disorder in people engaged in running and jumping sports. Aetiology of Achilles tendinopathy is complex and requires comprehensive research of contributing risk factors. There is relatively little research focussing on potential biomedical risk factors for Achilles tendinopathy. The purpose of this systematic review is to identify studies and summarise current knowledge of biomedical risk factors of Achilles tendinopathy in physically active people. Methods: Research databases were searched for relevant articles followed by assessment in accordance with PRISMA statement and standards of Cochrane collaboration. Levels of evidence and quality assessment designation were implemented in accordance with OCEBM levels of evidence and Newcastle-Ottawa Quality Assessment Scale, respectively. Results: A systematic review of the literature identified 22 suitable articles. All included studies had moderate level of evidence (2b) with the Newcastle-Ottawa score varying between 6 and 9. The majority (17) investigated genetic polymorphisms involved in tendon structure and homeostasis and apoptosis and inflammation pathways. Overweight as a risk factor of Achilles tendinopathy was described in five included studies that investigated non-genetic factors. COL5A1 genetic variants were the most extensively studied, particularly in association with genetic variants in the genes involved in regulation of cell-matrix interaction in tendon and matrix homeostasis. It is important to investigate connections and pathways whose interactions might be disrupted and therefore alter collagen structure and lead to the development of pathology. Polymorphisms in genes involved in apoptosis and inflammation, and Achilles tendinopathy did not show strong association and, however, should be considered for further investigation. Conclusions: This systematic review suggests that biomedical risk factors are an important consideration in the future study of propensity to the development of Achilles tendinopathy. The presence of certain medical comorbidities and genetic markers should be considered when contemplating the aetiology of Achilles tendinopathy. Further elucidation of biomedical risk factors will aid in the understanding of tendon pathology and patient risk, thereby informing prevention and management strategies for Achilles tendinopathy. Trial Registration: PROSPERO CRD42016036558
Achilles tendinopathy; Risk factors; Biomedical risk factors; Genetics
Increased BMI and adverse lipid profile may be
important biomarkers of Achilles tendinopathy.
Further research is required to confirm an association
between genetic variation, of genes encoding collagen
proteins and proteins involved in pathways of tendon
homeostasis and Achilles tendinopathy.
Genetic risk factors of Achilles tendinopathy may
be modified by geographic factors.
Literature Search Strategy
This systematic review was registered in the
international prospective register of systematic reviews
The quality of the included studies was evaluated
applying the Newcastle-Ottawa Quality Assessment Scale
(NOS) for case-control and cohort studies . This
assessment checklist is recommended by the Cochrane
Handbook for Systematic Reviews of Interventions [18, 21].
The NOS checklist assesses quality of the articles in three
domains: selection of the studied groups; comparability of
the groups and control for confounding factors; and
exposure for case-control studies or outcome for cohort studies.
Total maximum score is nine for both types of studies.
Results of the studies were critically analysed and presented
in the narrative form reporting odds ratios (OR) and
selected articles. Levels of evidence could be identified
according to the type of clinical question .
Results of the studies are described in narrative form,
and odds ratios and confidence intervals or relative risks
of developing Achilles tendinopathy are reported in
Table 2 where possible.
Levels of Evidence
Oxford Centre for Evidence-based Medicine (OCEBM)
levels of evidence was used as a guidance to evaluate
The selected studies focused on a diverse range of
biomedical risk factors for Achilles tendinopathy such as
Fig. 1 PRISMA flowchart of the study selection process
Abate et al. (2015) 
Abrahams et al. (2013) 
Brown et al. (2016) 
El Khoury et al. (2016) 
El Khoury et al. (2015) 
El Khoury et al. (2013) 
Gaida et al. (2009) 
Gaida et al. (2010) 
Gibbon et al. (2016) 
Hay et al. (2013) 
Longo et al. (2009) 
Mokone et al. (2005) 
Mokone et al. (2006) 
Nell et al. (2012) 
Owens et al. (2013) 
Posthumus et al. (2010) 
Raleigh (2009) 
Rickaby et al. (2015) 
Saunders et al. (2013) 
September et al. (2008) 
September et al. (2009) 
September et al. (2011) 
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exacerbated by physical load. Further elucidation of
biomedical risk factors will aid in the understanding of
tendon pathology and patient risk, thereby informing
prevention and management strategies for Achilles
Funding is provided by the Collaborative Research Network for Advancing
Exercise & Sports Science (CRN-AESS).
MK contributed to the conception and design of the review and analysis
and interpretation of the results and drafted the manuscript. NV contributed
to the conception and design of the review, analysis and draft revision. KA
contributed to the critical revision of the manuscript. DH contributed to the
critical revision of the manuscript. All authors read and approved the final
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Jarvinen TA , Kannus P , Maffulli N , Khan KM . Achilles tendon disorders: etiology and epidemiology . Foot Ankle Clin . 2005 ; 10 ( 2 ): 255 - 66 .
2. Padhiar N , Acharya N , Chan R , Davinii K , Crisp T , King J , et al. Achilles tendinopathy. Part 1-Pathophysiology and clinical features. SportEX Medicine . 2010 ; 45 : 23 - 30 .
3. Maffulli N. Overuse tendon conditions: time to change a confusing terminology . Arthroscopy: The Journal of Arthroscopic & Related Surgery . 1998 ; 14 ( 8 ): 840 - 3 .
4. Maffulli N , Sharma P , Luscombe KL . Achilles tendinopathy: aetiology and management . Journal Of The Royal Society Of Medicine . 2004 ; 97 ( 10 ): 472 - 6 .
5. Kader D , Saxena A , Movin T , Maffulli N. Achilles tendinopathy: some aspects of basic science and clinical management . Br J Sports Med . 2002 ; 36 ( 4 ): 239 .
6. Khan KM , Bonar F , Desmond PM , Cook JL , Young DA , Visentini PJ , et al. Patellar tendinosis (jumper's knee): findings at histopathologic examination , US, and MR imaging. Victorian Institute of Sport Tendon Study Group. Radiology . 1996 ; 200 ( 3 ): 821 - 7 .
7. Scott A , Khan K , Cook J , Duronio V. What is “inflammation”? Are we ready to move beyond Celsus? Br J Sports Med . 2004 ; 38 ( 3 ): 248 - 9 .
8. Abate M , Silbernagel KG , Siljeholm C , Di Iorio A , De Amicis D , Salini V , et al. Pathogenesis of tendinopathies: inflammation or degeneration? Arthritis Res Ther . 2009 ; 11 ( 3 ): 235 .
9. Cook J , Rio E , Purdam C , Docking S. Revisiting the continuum model of tendon pathology: what is its merit in clinical practice and research? British journal of sports medicine . 2016 :bjsports- 2015 - 095422 .
10. Fu S-C , Rolf C , Cheuk Y-C , Lui PP , Chan K-M . Deciphering the pathogenesis of tendinopathy: a three-stages process . BMC Sports Science , Medicine and. Rehabilitation . 2010 ; 2 ( 1 ): 30 .
11. Cook J , Purdam CR . Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy . Br J Sports Med . 2009 ; 43 ( 6 ): 409 - 16 .
12. Kvist M. Achilles tendon injuries in athletes . Ann Chir Gynaecol . 1991 ; 80 ( 2 ): 188 - 201 .
13. Kvist M. Achilles tendon injuries in athletes . Sports Med . 1994 ; 18 ( 3 ): 173 - 201 .
14. Lorimer A , Hume P. Achilles tendon injury risk factors associated with running . Sports Med . 2014 ; 44 ( 10 ): 1459 - 72 .
15. Dias Lopes A , Hespanhol Junior LC , Yeung SS , Pena Costa LO . What are the main running-related musculoskeletal injuries? Sports Med . 2012 ; 42 ( 10 ): 891 - 905 .
16. Gaida JE , Cook JL , Bass SL. Adiposity and tendinopathy. Disability & Rehabilitation . 2008 ; 30 ( 20 - 22 ): 1555 - 62 .
17. Lewis T , Cook J. Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature . Journal of Athletic Training (Allen Press) . 2014 ; 49 ( 3 ): 422 - 7 .
18. Higgins JP , Green S. Cochrane handbook for systematic reviews of interventions: Wiley Online Library . 2008 .
19. Moher D , Liberati A , Tetzlaff J , Altman DG . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . Ann Intern Med . 2009 ; 151 ( 4 ): 264 - 9 .
20. GA Wells BS , D O ' Connell , J Peterson , V Welch, M Losos, P Tugwell. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses . 200 [cited 3 March 2016 ]; Available from: http:// www.ohri.ca/programs/clinical_epidemiology/oxford.asp
21. Sara H , Downs NB . The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions . J Epidemiol Community Health . 1998 ; 52 : 377 - 84 .
22. Jeremy Howick ICJLL , Paul Glasziou , Trish Greenhalgh , Carl Heneghan , Alessandro Liberati , Ivan Moschetti , Bob Phillips , Hazel Thornton , Olive Goddard and Mary Hodgkinson . The Oxford levels of evidence 2. 2008 [cited; Available from: http://www.cebm. net/index.aspx?o=5653
23. Abrahams Y , Laguette MJ , Prince S , Collins M. Polymorphisms within the COL5A1 3′-UTR that alters mRNA structure and the MIR608 gene are associated with Achilles tendinopathy . Ann Hum Genet . 2013 ; 77 ( 3 ): 204 - 14 .
24. El Khoury L , Posthumus M , Collins M , Handley CJ , Cook J , Raleigh SM . Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: a genetic association study . J Sci Med Sport . 2013 ; 16 ( 6 ): 493 - 8 .
25. Hay M , Patricios J , Collins R , Branfield A , Cook J , Handley CJ , et al. Association of type XI collagen genes with chronic Achilles tendinopathy in independent populations from South Africa and Australia . Br J Sports Med . 2013 ; 47 ( 9 ): 569 - 74 .
26. Mokone GG , Gajjar M , September AV , Schwellnus MP , Greenberg J , Noakes TD , et al. The guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene is associated with achilles tendon injuries . Am J Sports Med . 2005 ; 33 ( 7 ): 1016 - 21 .
27. Mokone GG , Schwellnus MP , Noakes TD , Collins M. The COL5A1 gene and Achilles tendon pathology . Scand J Med Sci Sports . 2006 ; 16 ( 1 ): 19 - 26 .
28. Nell EM , Van Der Merwe L , Cook J , Handley CJ , Collins M , September AV . The apoptosis pathway and the genetic predisposition to Achilles tendinopathy . J Orthop Res . 2012 ; 30 ( 11 ): 1719 - 24 .
29. Posthumus M , Collins M , Cook J , Handley CJ , Ribbans WJ , Smith RKW , et al. Components of the transforming growth factor-β family and the pathogenesis of human achilles tendon pathology-a genetic association study . Rheumatology . 2010 ; 49 ( 11 ): 2090 - 7 .
30. Saunders CJ , Van Der Merwe L , Posthumus M , Cook J , Handley CJ , Collins M , et al. Investigation of variants within the COL27A1 and TNC genes and Achilles tendinopathy in two populations . J Orthop Res . 2013 ; 31 ( 4 ): 632 - 7 .
31. Raleigh SM . Variants within the MMP3 gene are associated with Achilles tendinopathy: possible interaction with the COL5A1 gene . Br J Sports Med . 2009 ; 43 ( 7 ): 514 - 20 .
32. September AV , Nell E-M , O'Connell K , Cook J , Handley CJ , Merwe L , et al. A pathway-based approach investigating the genes encoding interleukin-1β, interleukin-6 and the interleukin-1 receptor antagonist provides new insight into the genetic susceptibility of Achilles tendinopathy . Br J Sports Med . 2011 ; 45 ( 13 ): 1040 - 7 .
33. September AV . Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations . Br J Sports Med . 2009 ; 43 ( 5 ): 357 - 65 .
34. September AV , Posthumus M , Van Der Merwe L , Schwellnus M , Noakes TD , Collins M. The COL12A1 and COL14A1 genes and Achilles tendon injuries . Int J Sports Med . 2008 ; 29 ( 3 ): 257 - 63 .
35. El Khoury L , Posthumus M , Collins M , van der Merwe W , Handley C , Cook J , et al. ELN and FBN2 gene variants as risk factors for two sports-related musculoskeletal injuries . Int J Sports Med . 2015 ; 36 ( 4 ): 333 - 7 .
36. Brown KL , Seale KB , El Khoury LY , Posthumus M , Ribbans WJ , Raleigh SM , et al. Polymorphisms within the COL5A1 gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study . Journal Of Sports Sciences . 2016 ; 35 ( 15 ): 1 - 9 .
37. Gibbon A , Hobbs H , van der Merwe W , Raleigh SM , Cook J , Handley CJ , et al. The MMP3 gene in musculoskeletal soft tissue injury risk profiling: a study in two independent sample groups . Journal Of Sports Sciences . 2016 ; 35 ( 7 ): 655 - 662 .
38. El Khoury L , Ribbans WJ , Raleigh SM . MMP3 and TIMP2 gene variants as predisposing factors for Achilles tendon pathologies: attempted replication study in a British case-control cohort . Meta Gene . 2016 ; 9 : 52 - 5 .
39. Rickaby R , El Khoury L , Ribbans WJ , Raleigh SM . Variation within three apoptosis associated genes as potential risk factors for Achilles tendinopathy in a British based case-control cohort . Gene . 2015 ; 571 ( 2 ): 167 - 71 .
40. Owens BD , Wolf JM , Seelig AD , Jacobson IG , Boyko EJ , Smith B , et al. Risk factors for lower extremity tendinopathies in military personnel . Orthopaedic Journal of Sports Medicine . 2013 ; 1 ( 1 ): 1 - 8 .
41. Abate M , Salini V , Schiavone C. Achilles tendinopathy in elderly subjects with type II diabetes: the role of sport activities . Aging Clin Exp Res . 2015 ; 28 ( 2 ): 355 - 358 .
42. Longo UG , Rittweger J , Garau G , Radonic B , Gutwasser C , Gilliver SF , et al. No influence of age, gender, weight, height, and impact profile in Achilles tendinopathy in masters track and field athletes . Am J Sports Med . 2009 ; 37 ( 7 ): 1400 - 5 .
43. Gaida JE , Alfredson L , Kiss ZS , Wilson AM , Alfredson H , Cook JL. Dyslipidemia in achilles tendinopathy is characteristic of insulin resistance . Med Sci Sports Exerc . 2009 ; 41 ( 6 ): 1194 - 7 .
44. Gaida JE , Alfredson H , Kiss ZS , Bass SL , Cook JL . Asymptomatic Achilles tendon pathology is associated with a central fat distribution in men and a peripheral fat distribution in women: a cross sectional study of 298 individuals . BMC Musculoskelet Disord . 2010 ; 11 : 41 .
45. Group OLoEW. The Oxford 2011 levels of evidence . Oxford, UK: Oxford centre for evidence-based medicine; 2011.
46. Abate M , Oliva F , Schiavone C , Salini V. Achilles tendinopathy in amateur runners: role of adiposity (tendinopathies and obesity) . Muscles, Ligaments And Tendons Journal . 2012 ; 2 ( 1 ): 44 - 8 .
47. Tilley BJ , Cook JL , Docking SI , Gaida JE . Is higher serum cholesterol associated with altered tendon structure or tendon pain? A systematic review . British journal of sports medicine . 2015 :bjsports- 2015 - 095100 .
48. Wright AF . Genetic variation: polymorphisms and mutations . Wiley Online Library . 2005 .
49. Maffulli N , Reaper JA , Waterston SW , Ahya R. ABO blood groups and Achilles tendon rupture in the Grampian region of Scotland . Clin J Sport Med . 2000 ; 10 ( 4 ): 269 - 71 .
50. Leppilahti J , Puranen J , Orava S. ABO blood group and Achilles tendon rupture . Ann Chir Gynaecol . 1995 ; 1995 : 369 - 71 .
51. Rickert M , Wang H , Wieloch P , Lorenz H , Steck E , Sabo D , et al. Adenovirusmediated gene transfer of growth and differentiation factor-5 into tenocytes and the healing rat Achilles tendon . Connect Tissue Res . 2005 ; 46 ( 4-5 ): 175 - 83 .
52. Mansfield JC , Holden H , Tarlow JK , Di Giovine FS , McDowell TL , Wilson AG , et al. Novel genetic association between ulcerative colitis and the antiinflammatory cytokine interleukin-1 receptor antagonist . GasrtoenterologyBaltimore then Philadelphia . 1994 ; 106 : 637 -.
53. Langdahl BL , Løkke E , Carstens M , Stenkjaer LL , Eriksen EF . Osteoporotic fractures are associated with an 86‐base pair repeat polymorphism in the interleukin‐1‐receptor antagonist gene but not with polymorphisms in the interleukin‐1β gene . J Bone Miner Res . 2000 ; 15 ( 3 ): 402 - 14 .
54. Olofsson PS , Sheikine Y , Jatta K , Ghaderi M , Samnegård A , Eriksson P , et al. A functional interleukin-1 receptor antagonist polymorphism influences atherosclerosis development . The interleukin-1 beta: interleukin-1 receptor antagonist balance in atherosclerosis . Circ J . 2009 ; 73 ( 8 ): 1531 - 6 .
55. Landvik NE , Hart K , Skaug V , Stangeland LB , Haugen A , Zienolddiny S. A specific interleukin-1B haplotype correlates with high levels of IL1B mRNA in the lung and increased risk of non-small cell lung cancer . Carcinogenesis . 2009 ; 30 ( 7 ): 1186 - 92 .
56. Fishman D , Faulds G , Jeffery R , Mohamed-Ali V , Yudkin JS , Humphries S , et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL6 transcription and plasma IL-6 levels, and an association with systemiconset juvenile chronic arthritis . J Clin Investig . 1998 ; 102 ( 7 ): 1369 .
57. Namipashaki A , Razaghi-Moghadam Z , Ansari-Pour N. The essentiality of reporting Hardy-Weinberg equilibrium calculations in population-based genetic association studies . Cell Journal (Yakhteh) . 2015 ; 17 ( 2 ): 187 .
58. Scotia N. Explaining odds ratios . J Can Acad Child Adolesc Psychiatry . 2010 ; 19 : 227 .
59. Gaida JE , Bagge J , Purdam C , Cook J , Alfredson H , Forsgren S. Evidence of the TNF-α system in the human Achilles tendon: expression of TNF-α and TNF receptor at both protein and mRNA levels in the tenocytes . Cells Tissues Organs . 2012 ; 196 ( 4 ): 339 - 52 .
60. Porter AG , Jänicke RU . Emerging roles of caspase-3 in apoptosis . Cell Death Differ . 1999 ; 6 ( 2 ): 99 - 104 .