Sports Med DOI 10.1007/s40279-014-0200-z

SYSTEMATIC REVIEW

Predictors of Primary Achilles Tendon Ruptures Femke M. A. P. Claessen • Robert-Jan de Vos Max Reijman • Duncan E. Meuffels

•

 Springer International Publishing Switzerland 2014

Abstract Background The Achilles tendon is the strongest tendon in the human body. The incidence of Achilles tendon ruptures appears to be increasing. Objectives The aim of this review was to systematically summarize predictors influencing Achilles tendon rupture (ATR) risk. Methods A systematic literature search was performed of reported determinants influencing the ATR risk. Studies were eligible if there was: (i) description of determinants predicting ATR; (ii) an outcome defined as ATR; (iii) any study design with at least ten adults included with ATR; (iv) use of statistical tests regarding differences between patients with an ATR and healthy controls; (v) a full text article available; (vi) an article written in English, German or Dutch. Quality assessment was done using a standardized criteria set. Best-evidence synthesis was performed. Results We included 31 studies, of which two (6.5 %) were considered high-quality studies. Moderate evidence was found for increased ATR risk and decreased fibril size of Achilles tendon. Conclusion Based on the results of this systematic review there is moderate evidence that decreased tendon fibril size increases the ATR risk. There is limited evidence for many other factors, some of which are modifiable, such as

F. M. A. P. Claessen
R.-J. de Vos
M. Reijman
D. E. Meuffels (&) Department of Orthopaedic Surgery, Erasmus MC, University Medical Centre Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands e-mail: [email protected] R.-J. de Vos Department of Sports Medicine, The Hague Medical Centre, Leidschendam, The Netherlands

increased body weight, oral corticosteroid use and quinolone use and living in an urban area, and therefore may be of interest in future studies. Furthermore, these results showed that more high-quality studies are needed for evaluating the determinants influencing the ATR risk.

1 Introduction The prevalence of Achilles tendon rupture is 6–37/100,000 person years [1–6] and the incidence appears to be increasing [3, 7]. Most Achilles tendon ruptures are associated with sport activities [8–10]. A rising incidence could be partly explained by increasing participation in sport activities by the general population [9]. An Achilles tendon rupture can be career threatening for athletes as one-third of the national sport players who suffered an Achilles tendon rupture could never play at the same sports level again [11]. The most common location for Achilles tendon rupture is 3–6 cm above the calcaneal insertion [12, 13]. This can be partly explained by peak stresses in this midportion area of approximately 70 mega pascal (MPa), while most tendons experience peak stresses below 30 MPa [14]. These biomechanical models can explain why the Achilles tendon is prone to rupturing, but it remains largely unknown which determinants influence the risk of an Achilles tendon rupture. There are several studies evaluating these predictors for Achilles tendon ruptures. Several intrinsic and extrinsic risk factors are possibly associated with Achilles tendon ruptures. Modifiable risk factors, for example higher body mass index (BMI), are especially clinically relevant to counsel and possibly treat patients potentially at risk, to prevent an Achilles tendon rupture. A systematic review regarding the determinants associated with Achilles tendon ruptures has never been performed. Therefore, we aimed to systematically review studies

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F. M. A. P. Claessen et al.

investigating determinants influencing the risk of Achilles tendon ruptures.

2 Methods 2.1 Eligibility Criteria Studies were eligible when there was (i) a description of determinants predicting Achilles tendon rupture; (ii) an outcome defined as Achilles tendon rupture; (iii) any study design with at least ten adults included with Achilles tendon rupture; (iv) use of statistical tests regarding significant differences between patients with an Achilles tendon rupture and healthy controls; (v) a full text article available; (vi) an article written in English, German, Dutch or Spanish. A study was excluded if the article was not an original study. Animal studies were also excluded.

If there was a difference in opinion on quality assessment, consensus was reached by consulting a third reviewer (DM). For the quality assessment we used a standardized set of criteria based on modified questions of existing quality assessment tools [15–17] (Table 1). When the criterion was met in the article, one point was given, otherwise zero points. Zero points were also given when information concerning the specific criterion was not mentioned in the article. We assessed the methodological quality of all studies, using modified questions from existing quality assessment tools [15–17]. A maximum score of ten points could be obtained. According to the total quality score, articles were considered of high methodological quality if a total score of six points or higher had been awarded, combined with a score of one point each for questions six, seven, eight and ten [18]. 2.5 Data Extraction

2.2 Search Strategy and Information Sources To identify studies that investigated the predictors influencing Achilles tendon ruptures, we searched the following databases, up to 2 February 2014: EMBASE, MEDLINE OvidSP, Web of Science, Cochrane Central, PubMed Publisher and Google Scholar. The following combined key words were used: (‘achilles tendon rupture’/de OR ((‘tendon injury’/de OR ‘tendon rupture’/de OR rupture/de) AND (‘achilles tendon’/de OR ‘achilles tendinitis’/de)) OR (achill* NEAR/3 (rupture* OR injur* OR tear* OR disorder*)):ab,ti) AND (risk/exp OR Etiology/de OR ‘tendon injury’/exp/dm_et OR histopathology/ de OR (risk* OR etiolog* OR etiopatholog* OR aetiopatholog* OR aetiolog* OR causal* OR causat* OR cause OR predipos* OR precipitat* OR reinforce* OR enabling OR pathogenes* OR etiopathogenes* OR aetiopathogenes* OR histopatholog* OR ‘associated with’ OR ‘result from’ OR ‘owing to’):ab,ti) NOT ([animals]/lim NOT [humans]/lim). The EMBASE search strategy was transferred into similar search strategies in MEDLINE OvidSP, Web of Science, Cochrane Central, PubMed Publisher and Google Scholar. References of relevant articles were checked for additional articles and all bibliographies of the included articles were also hand searched to identify further relevant literature. 2.3 Study Selection Study selection was assessed by two independent reviewers (FC and DM). Disagreements were solved by consensus. 2.4 Methodological Quality Assessment The quality of each included paper was assessed by two independent reviewers (FC and RV).

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Data extraction was performed by one author (FC). The following data were extracted: study population (patient characteristics, population size, sex and age), design of study, diagnosis of Achilles tendon rupture, determinants measured, outcome (method of assessment, blinding, reproducibility), association between determinant and outcome. The determinants were grouped into patient characteristics (age, sex, prehistory, body mass index (BMI), height, medicine, ankle/foot position, pre-existing disease or element of tendon changes, genetic factors and environmental factors. 2.6 Level of Evidence Synthesis Because the observational studies were heterogeneous with regard to study population, methodological quality, duration of follow-up and measurement of determinants, we followed standard practice and refrained from statistically pooling the data and performed a ‘best-evidence’ synthesis based on the study of van Tulder et al. [18]. Strong evidence was defined as two or more studies with high quality and generally consistent findings in all studies (C75 % of the studies reported consistent findings). Moderate evidence was defined as one high-quality study and two or more low-quality studies and generally consistent results (C75 % of the studies reported consistent findings). Limited evidence was defined as generally consistent findings in one or more low-quality studies (C75 % of the studies reported consistent findings). Conflicting evidence was defined as \75 % of the studies reported consistent findings. If no study could be found, the level was defined as ‘no evidence’.

Predictors of Achilles Tendon Ruptures Table 1 List of criteria used for methodological quality assessment

Criteria

Response

1. A clearly stated aim

Did they have a ‘study question’ or ‘main aim’ or ‘objective’? The question addressed should be precise and relevant in light of available literature To be scored adequate the aim of the study should be coherent with the ‘Introduction’ of the paper Did the authors say: ‘consecutive patients’ or ‘all patients during period from … to….’ or ‘all patients fulfilling the inclusion criteria’?

2. Inclusion of consecutive patients

3. A description of inclusion and exclusion criteria

Did the authors report the inclusion and exclusion criteria?

4. Inclusion of patients

Did the authors report how many eligible patients agreed to participate (i.e., gave consent)?

5. Prospective collection of data. Data were collected according to a protocol established before the beginning of the study

Did they say ‘prospective’, ‘retrospective’ or ‘followup’?

6. Outcome measures

Did they report the association between the determinant and Achilles tendon ruptures as outcome? F.i valid outcome measures for Achilles tendon rupture are physical examination (Thompson test), ultrasound or MRI

7. Unbiased assessment of the study outcome and determinants

To be judged as adequate, the following two aspects had to be positive:

The study is NOT PROSPECTIVE when it is a chart review, database review, clinical guideline, or practical summaries

Outcome and determinants had to be measured independently The outcome and determinants for both cases and controls had to be assessed in the same way 8. Were the determinant measures used accurate (valid and reliable)?

For studies where the determinant measures are shown to be valid and reliable, the question should be answered adequate. For studies that refer to other work that demonstrates the determinant measures are accurate, the question should be answered as adequate

9. Loss to follow-up

To be judged as adequate the following two aspects had to be positive: Did they report the losses to follow-up? Loss to follow-up was \20 %

10. Adequate statistical analyses

To be judged as adequate the following two aspects had to be positive: There must be a description of the relationship between the determinant and Achilles tendon rupture (with information about the statistical significance)

F.i functional index, MRI magnetic resonance imaging

3 Results 3.1 Identification and Selection of the Literature From an initial 1,515 potentially relevant studies identified after duplication, 958 articles were retrieved from EMBASE, 308 from MEDLINE, 11 from Cochrane

Was there adjustment for possible confounders (age, race) by multivariate analysis?

Central, 139 from Web of Science, 88 from Google Scholar and 11 from PubMed publisher. No articles were retrieved after checking the references of relevant articles. Of these, 1,445 articles were excluded based on title and abstract. 70 papers were retrieved for detailed assessment; ten were excluded because of study design, five were letters to the editor and eight studies included less than ten

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1515 potentially relevant publications identified from electronic search. EMBASE: 958 MEDLINE: 308 Web of Science: 139 PubMed publisher: 11 Google Scholar 88 Cochrane Central: 11

1445 studies excluded on the basis of title and abstract

70 publications retrieved for more detailed assessment 39 articles did not fulfill the inclusion criteria because of the following reasons: 10 articles: review 2 articles: no full text available 5 articles: letter to the editor 8 articles: included less than ten patients 9 articles: ATR not outcome 5 articles: no use of statistical tests regarding significant differences between patients with an ATR and healthy controls 31 eligible for inclusion

Fig. 1 Flow diagram of study selection and exclusion stages. ATR Achilles tendon rupture

patients. In nine studies, Achilles tendon rupture was not an outcome. Five studies did not use statistical tests regarding significant differences between groups. A full text was not available for two articles. Consequently, a total of 31 studies were included (Fig. 1).

risk of bias. For the specific items for opportunity of bias there was disagreement on 5 out of the 310 assessed items (1.6 %), for which consensus was reached with a third reviewer. 3.3 Methodology

3.2 Quality Assessment According to the predefined quality criteria, two studies (6.5 % of the studies included) were considered as having high quality [19, 20]. Magnusson et al. [19] evaluated the association between Achilles tendon rupture and anteriorposterior tendon diameter. Raleigh et al. [19, 20] described the association between Achilles tendon rupture and presence of matrix metalloproteinase (MMP) 3. The quality assessment scores are shown in Table 2. For all the studies included, the independent assessments of the reviewers corresponded on whether it was a study with low or high

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Five of the selected studies were follow-up studies, 12 were case–control studies and 14 were cross-sectional studies. No randomized controlled trials (RCTs) were available. The mean age of the included patients ranged from 36 to 69 years. The follow-up time of the cohorts ranged from 1 to 45 years. The most common method of diagnosis was establishment during surgery. Table 3 shows a summary of studies evaluating the determinants influencing the risk of Achilles tendon rupture. Table 4 illustrates an overview of determinants influencing the risk of Achilles tendon ruptures with their level of evidence.

Predictors of Achilles Tendon Ruptures Table 2 Quality assessment scores Study

Criteria 1

Total 2

3

4

5

6

7

8

9

10

Bleakney et al. (2002) [37]

1

1

1

0

0

1

0

0

0

1

5

Corrao et al. (2006) [21]

1

1

1

0

0

0

1

0

0

1

5

Davis et al. (1999) [10]

1

1

1

1

0

1

0

0

0

1

6

Hansen et al. (2013) [34]

1

0

1

0

0

1

0

1

0

0

4

Jarvinen et al. (2004) [36]

1

1

0

0

0

1

0

1

0

0

4

Jones et al. (2006) [40]

1

0

0

0

0

1

0

0

0

0

2

Jozsa et al. (1989) [26] Kettunen et al. (2006) [24]

1 0

1 1

0 1

1 0

0 1

1 0

0 1

0 1

0 1

0 0

4 6

Kraemer et al. (2012) [31]

1

0

1

0

0

0

1

0

0

1

4

Kujala et al. (2005) [46]

0

1

1

1

0

0

1

1

0

1

6

Kujala et al. (1992) [43]

1

0

0

0

0

1

1

1

0

0

4

Legerlotz et al. (2012) [42]

1

0

0

0

0

1

0

0

0

0

2

Leppilahti et al. (1998) [39]

1

1

0

1

0

1

0

1

0

0

5

Maffulli et al. (2000) [38]

1

0

0

0

0

1

1

0

0

0

3

Maffulli et al. (2000) [44]

1

1

0

0

0

1

0

0

0

0

3

Maffulli et al. (2000) [35]

1

0

0

0

0

1

0

1

0

1

4

Maffulli et al. (1998) [32]

1

1

0

1

0

1

0

0

0

0

4

Magnusson et al. (2002) [19]

1

1

0

0

0

1

1

1

0

1

6

Nyyssonen et al. (2008) [7]

1

1

0

1

0

0

0

1

0

0

4

Owens et al. (2007) [27]

1

1

0

1

0

0

1

1

0

1

6

Petersen et al. (2004) [41]

1

0

1

0

0

1

1

1

0

0

5

Posthumus et al. (2009) [25] Raikin et al. (2013) [30]

1 1

0 1

0 1

0 0

0 0

0 1

1 0

1 1

0 0

1 0

4 5

Raleigh et al. (2009) [20]

1

0

1

0

0

1

1

1

0

1

6

Raunest et al. (1990) [45]

1

0

1

1

0

1

0

0

0

0

4

Seeger et al. (2006) [28]

1

1

0

1

0

0

1

1

0

1

6

Sode et al. (2007) [47]

1

1

0

1

0

0

1

1

0

1

6

Tallon et al. (2001) [33]

1

1

1

0

0

1

1

0

0

0

5

Van der Linden et al. (2003) [22]

1

1

1

1

0

0

1

1

0

1

7

Vosseller et al. (2013) [29]

1

1

1

0

0

1

0

1

0

0

5

Wise et al. (2012) [23]

1

1

1

1

0

0

1

1

0

1

7

Each item scored one point if it met the methodological criteria listed in Table 1. If not, or the item was not reported, a score of zero was assigned

3.4 Non-Modifiable Predictors 3.4.1 Patient Characteristics 3.4.1.1 Age Limited evidence was found for higher age increasing the risk of Achilles tendon ruptures. Five low-quality studies assessed the effect of age on Achilles tendon ruptures [21–25]. In the studies of Corrao et al. [21] and van der Linden et al. [22], an increased risk of Achilles tendon rupture was found for an age above 60 years. One study showed an increased risk of Achilles tendon rupture above 45 years [24]. One study reported no significant effect of higher age on Achilles tendon ruptures [23].

One low-quality study showed that the mean age of patients who had an Achilles tendon rupture was significant lower than in other tendon ruptures [26]. Limited evidence was found. 3.4.1.2 Race Two low-quality studies investigated the effect of race on Achilles tendon ruptures [10, 27]. Both studies showed an increased Achilles tendon rupture risk for Black race compared with Caucasian race. In summary, limited evidence was found for Black race increasing the Achilles tendon rupture risk. 3.4.1.3 Sex Four low-quality studies investigated the effect of sex on Achilles tendon ruptures [22, 28–30].

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123

Finland [24]

2006

Kettunen et al.

Hungary [26]

1989

Jozsa et al.

UK [40]

2006

Jones et al.

Finland [36]

2004

Jarvinen et al.

Denmark [34]

Hansen et al. 2013

USA [10]

1999

Davis et al.

Italy [21]

2006

England [37] Corrao et al.

C

C

CS

CC

CC

CS

CC

CC

Bleakney et al.

2002

Study type

Study

78 (100)

292 (82.9)

12

22

17 (88)

865 (100)

22,194 (36.5)

70 (80)

Males, n (%)

777

457

11

10 controls

17 contralateral tendons

10 controls

–

104,906

70 contralateral tendons

70 controls

Referent group (n)

58.3

35.2

42

39.8

34.8

55.9

49.3

Age, mean (years)

16

13

–

–

–

–

–

–

Followup (years)

Surgery

Surgery

Surgery

Surgery

Clinical

US

Diagnosis

x

x

x

x

Patient characteristics

Table 3 Included studies on the determinants influencing the risk of Achilles tendon rupture

x

Medication

Ankle/ foot position

x

Genetic factors

x

x

x

Pre-existing disease or changed tendon

Environmental factors

6

4

2

4

4

6

5

5

Quality score (points)

F. M. A. P. Claessen et al.

Scotland [35]

2000

Maffuli et al.

Scotland [44]

2000

Maffuli et al.

Scotland [38]

2000

Maffuli et al.

Finland [39]

1998

Leppilahti et al.

2012 UK [42]

Legerlotz et al.

Hungary [43]

1992

Kujala et al.

Finland [46]

2005

Kujala et al.

Germany [31]

CS

CS

CS

CC

CS

CC

C

CS

Kraemer et al.

2012

Study type

Study

Table 3 continued

22 (86.4)

78

38 (71.1)

101

18 (77.7)

86 (83.7)

785 (100)

60 (73)

Males, n (%)

–

–

–

87

9

5,536

416

–

Referent group (n)

46.3

45.3

46.3

36.1

69

40

Age, mean (years)

–

–

–

–

–

–

45

–

Followup (years)

Surgery

Surgery

Surgery

Surgery

Surgery

Diagnosis

x

x

Patient characteristics

x

Medication

x

Ankle/ foot position

x

x

x

Genetic factors

x

x

Pre-existing disease or changed tendon

x

Environmental factors

4

3

3

5

2

4

6

4

Quality score (points)

Predictors of Achilles Tendon Ruptures

123

123

USA [30]

2013

Raikin et al.

South Africa [25]

2009

Posthumus et al.

Germany [41]

2004

Petersen et al.

USA [27]

2007

Owens et al.

Finland [7]

2008

Nyyssonen et al.

Denmark [19]

Magnusson et al. 2002

Scotland [32]

CS

CC

CC

CS

CS

CS

CC

Maffuli et al.

1998

Study type

Study

Table 3 continued

406 (83)

41

20 (65)

72,767

7,375 (79)

10 [60]

102

Males, n (%)

0

125

20

–

–

–

128

Referent group (n)

46.4

35

42

46

Age, mean (years)

–

–

–

–

–

–

–

Followup (years)

Surgery

Surgery

Surgery

Diagnosis

x

x

x

x

x

Patient characteristics

Medication

Ankle/ foot position

x

x

Genetic factors

x

Pre-existing disease or changed tendon

x

x

Environmental factors

5

4

5

6

4

6

4

Quality score (points)

F. M. A. P. Claessen et al.

C

CS

CC

C

CS

CC

7,685 (69.1)

468 (79)

1,367

35

28,262

947

65 (81.5)

39

Males, n (%)

7,685

–

50,000

16

–

18,940

–

98

Referent group (n)

36.3

46.5

48

38.4

39.4

Age, mean (years)

1

–

–

3

–

–

–

–

Followup (years)

Surgery

Some surgery

Surgery

US/ Surgery

Diagnosis

– No data

C Cohort study, CC case control study, CS cross-sectional study, US ultrasound

UK [23]

2012

Wise et al.

2013 USA [29]

Vosseller et al.

[22]

UK

2003

Van der Linden et al.

Scotland [33]

2001

Tallon et al.

2007 Denmark [47]

Sode et al.

USA [28]

2006

Seeger et al.

Germany [45]

1990

Raunest et al.

South Africa [20]

CS

CC

Raleigh et al.

2009

Study type

Study

Table 3 continued

x

x

x

x

x

Patient characteristics

x

x

x

x

Medication

Ankle/ foot position

x

x

Genetic factors

x

x

x

Pre-existing disease or changed tendon

Environmental factors

7

5

7

5

6

6

4

6

Quality score (points)

Predictors of Achilles Tendon Ruptures

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F. M. A. P. Claessen et al. Table 4 Determinants influencing the risk of Achilles tendon ruptures Determinants

Study (first author and reference number)

Best-evidence synthesis

Age

Corrao [ 60 years : [21], Kettunen [ 45 years : [24], Posthumus : [25], van der Linden [ 60 years : [22], Wise = [23], Jozsa : [26]

Limited evidence

Black race Male sex

Davis : [10], Owens : [27] Seeger : [28], van der Linden : [22], Vosseller = [29], Raikin : [30]

Limited evidence Limited evidence

Patient characteristics

Obesity

Posthumus : [25], Seeger : [28], van der Linden = [22]

Limited evidence

Negative family history

Kraemer = [31]

Limited evidence

Renal failure

Seeger = [28], van der Linden = [22], Wise = [23]

Limited evidence

Renal transplantees

van der Linden : [22]

Limited evidence

Diabetes mellitus

Kraemer = [31], van der Linden = [22], Seeger = [28], Wise = [23]

Limited evidence

Inflammatory bowel disease

Van der Linden : [22]

Limited evidence

Psoriasis

Van der Linden = [22]

Limited evidence

Arterial hypertension

Kraemer = [31]

Limited evidence

Cardiac diseases

Kraemer = [31]

Limited evidence

Hypercholesterolemia

Kraemer = [31], van der Linden : [22]

Conflicting evidence

Skin or soft tissue infections

Seeger = [28]

Limited evidence

Ipsilateral sciatic pain

Maffuli : [32]

Limited evidence

COPD

Seeger = [28]

Limited evidence

Asthma Systemic lupus

Seeger = [28] Seeger = [28]

Limited evidence Limited evidence

Hyperparathyroid

Seeger = [28]

Limited evidence

Hospitalization with infection

Seeger = [28]

Limited evidence

Genitourinary infection

Seeger = [28]

Limited evidence

Other infection

Seeger = [28]

Limited evidence

Sports activity

Raunest = [45], Kujala : [46], Jozsa : [26]

Conflicting evidence

Trauma

Seeger : [28]

Limited evidence

Autoimmune arthritis

Van der Linden : [22]

Limited evidence

Infectious arthritis

Van der Linden : [22]

Limited evidence

Spondyloarthropathies

Van der Linden = [22]

Limited evidence

Gout

Van der Linden = [22]

Limited evidence

Pre-existing disease or changes to tendon

Rheumatoid arthritis

Seeger : [28]

Limited evidence

Nonarticular rheumatism

Van der Linden = [22]

Limited evidence

Tendinopathy

Tallon : [33]

Limited evidence

General osteoarthritis Tendinitis

Van der Linden : [22] Seeger : [28]

Limited evidence Limited evidence

Achilles bursitis

Seeger : [28]

Limited evidence

Enthesopathy

Seeger : [28]

Limited evidence

Orthopedic visit

Seeger : [28]

Limited evidence

Podiatry visit

Seeger : [28]

Limited evidence

Past history of musculoskeletal-related disorder

Van der Linden : [22]

Limited evidence

General osteoarthritis

Van der Linden : [22]

Limited evidence

Less collagen type 3

Maffuli : [35]

Limited evidence

More collagen type 1

Maffuli : [35]

Limited evidence

Less collagen content

Hansen : [34]

Limited evidence

Less lysyl pyridinoline

Hansen = [34] Hansen = [34]

Limited evidence Limited evidence

Less hydroxylysyl pyridinoline

123

Predictors of Achilles Tendon Ruptures Table 4 continued Determinants

Study (first author and reference number)

Best-evidence synthesis

Less pentosidine

Hansen = [34]

Limited evidence

Lower Young’s modulus

Hansen : [34]

Limited evidence

Anterior posterior diameter

Bleakney : [37]

Limited evidence

Decreased fibril size

Magnusson : [19]

Moderate evidence

Lower collagen fiber diameter

Jarvinen : [36]

Limited evidence

Lower crimp angle

Jarvinen : [36]

Limited evidence

More separation of collagen fibers

Maffulli : [35]

Limited evidence

Increased waviness of collagen fibers

Maffulli : [35]

Limited evidence

Loss of collagen fiber arrangement Decreased number of nuclei in tenocytes

Maffulli : [35] Maffulli : [35]

Limited evidence Limited evidence

More rounded nuclei in tenocytes

Maffulli : [35]

Limited evidence

Increased cellularity

Maffulli : [35]

Limited evidence

More vascular bundles

Maffulli : [35]

Limited evidence

Less collagen stainability

Maffulli : [35]

Limited evidence

More glycosaminoglycans stainability

Maffulli : [35]

Limited evidence

Underpronating alignment of ankle

Leppilathi : [39]

Limited evidence

Longitudinal high arch

Leppilathi : [39]

Limited evidence Limited evidence

Oral corticosteroids

Corrao : [21], Seeger : [28], Sode : [47], Wise : [23], van der Linden : [22] Seeger : [28], van der Linden : [22]

Limited evidence

Corticosteroid injections

Seeger = [28]

Limited evidence

Ankle/foot position

Medication Quinolone

Salicylates

Kraemer = [31]

Limited evidence

Other antibacterials

Seeger = [28], van der Linden = [22]

Limited evidence

Genetic factors COL1A1 Sp1-binding site polymorphism

Posthumus = [25], Legerlotz = [42]

Limited evidence

VEGF

Petersen = [41], Legerlotz : [42]

Conflicting evidence

Higher COX2 expression

Legerlotz : [42]

Limited evidence

Higher OSM expression

Legerlotz : [42]

Limited evidence

Higher LIF expression

Legerlotz : [42]

Limited evidence

Higher IL6 expression

Legerlotz : [42]

Limited evidence

Lower IL6R expression

Legerlotz : [42]

Limited evidence

Legerlotz = [42]

Limited evidence

ABO blood group distribution

Kujala : [43], Maffulli = [44]

Conflicting evidence

MMP3 MMP1

Raleigh = [20], Jones : [40] Jones : [40]

Moderate evidence Conflicting evidence

MMP7

Jones : [40]

Limited evidence

MMP9

Jones : [40]

Limited evidence

MMP11

Jones : [40]

Limited evidence

MMP14

Jones : [40]

Limited evidence

Higher CNTF expression

MMP17

Jones = [40]

Limited evidence

MMP19

Jones : [40]

Limited evidence

MMP24

Jones : [40]

Limited evidence

MMP25

Jones : [40]

Limited evidence

MMP28

Jones : [40]

Limited evidence

ADAMTS4

Jones : [40]

Limited evidence

ADAMTS7

Jones : [40]

Limited evidence

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F. M. A. P. Claessen et al. Table 4 continued Determinants

Study (first author and reference number)

Best-evidence synthesis

ADAMTS13

Jones : [40]

Limited evidence

TIMP1

Jones : [40]

Limited evidence

TIMP2

Jones : [40]

Limited evidence

TIMP3

Jones : [40]

Limited evidence

TIMP4

Jones : [40]

Limited evidence

ADAM8

Jones : [40]

Limited evidence

ADAM12

Jones : [40]

Limited evidence

ADAM17

Jones : [40]

Limited evidence

Kraemer = [31]

Limited evidence

Urban areas

Nyyssonen : [7]

Limited evidence

Seasonal factors

Raikin : [30]

Limited evidence

Environmental factors Smoking

= no association, : positive association, ADAM a disintegrin and metalloproteinase, ADAMTS a disintegrin and metalloproteinase thrombospondin motifs, CNTF ciliary neurotrophic factor, COPD chronic obstructive pulmonary disease, COX cyclo-oxygenase, IL interleukin, ILR interleukin receptor, LIF leukemia inhibitor factor, MMP matrix metalloproteinase, OSM oncostatin M, TIMP tissue inhibitor of metalloproteinase, VEGF vascular endothelial growth factor

Vosseller et al. showed no association between male sex and Achilles tendon ruptures [29]. Three studies showed an increased risk for Achilles tendon rupture if the patient was male. This was regarded as limited evidence [22, 28–30]. 3.4.1.4 Renal Failure Three low-quality studies investigated the effect of renal failure on Achilles tendon ruptures [22, 23, 28]. All studies reported no significant change in risk. Limited evidence was found. One low-quality study evaluated the effect of renal transplants on Achilles tendon ruptures [28]. No increase in Achilles tendon rupture risk was shown. Limited evidence was found. 3.4.1.5 Diabetes Mellitus Four low-quality studies assessed the effect of diabetes mellitus on Achilles tendon ruptures [22, 23, 28, 31]. In the study of Kraemer et al. [31], the effect of type II diabetes on Achilles tendon rupture risk was assessed. In the other studies, no diabetes type was described. All studies had similar results; diabetes mellitus did not affect the risk of an Achilles tendon rupture. Limited evidence was found. 3.4.1.6 Other Non-Musculoskeletal Diseases One lowquality study assessed the effect of arterial hypertension, cardiac diseases or a negative family history of Achilles tendon ruptures on Achilles tendon ruptures. All of the investigated factors did not affect the Achilles tendon rupture risk [31]. Limited evidence was found. One low-quality study investigated the effect of ipsilateral sciatic pain and Achilles tendon rupture. Ipsilateral sciatic pain increased the Achilles tendon rupture risk [32]. Limited evidence was found.

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One low-quality study investigated the effect of inflammatory bowel disease or psoriasis on Achilles tendon ruptures. Psoriasis and inflammatory bowel disease did not affect the Achilles tendon rupture risk [22]. Limited evidence was found. Renal transplants in the past medical history significantly increased the Achilles tendon rupture risk [29]. Limited evidence was found. One low-quality study evaluated the effect of skin or softtissue infections, chronic obstructive pulmonary disease (COPD), asthma, systematic lupus, hyperparathyroid, hospitalization with infection, genitourinary infection or other infections on Achilles tendon ruptures [28]. All determinants described above did not significantly influence the Achilles tendon rupture risk. Limited evidence was found. 3.4.1.7 Trauma One low-quality study evaluated the effect of blunt Achilles tendon trauma on Achilles tendon ruptures [28]. Based on the study, a significant increase was found. Limited evidence was shown. 3.4.2 Pre-Existing Musculoskeletal Disease or Elements of Tendon Change 3.4.2.1 Pre-Existing Musculoskeletal Disease One lowquality study evaluated the effect of diagnosed tendinitis, Achilles bursitis, enthesopathy, orthopedic visit or podiatry visit in past medical history and presence of rheumatoid arthritis on risk of Achilles tendon ruptures [28]. For all determinants an increased Achilles tendon rupture risk was found. Limited evidence was shown. One low-quality study assessed the effect of autoimmune arthritis, infectious arthritis, spondylarthropathies,

Predictors of Achilles Tendon Ruptures

gout, non-articular rheumatism or general osteoarthritis on Achilles tendon ruptures [22]. Autoimmune arthritis, osteoarthritis and infectious arthritis showed a significant increase in Achilles tendon rupture risk. Gout, non-articular rheumatism and spondylarthropathies were not associated with Achilles tendon rupture. Limited evidence was found. One low-quality study investigated the effect of tendinopathy on Achilles tendon rupture risk [33]. Tendinopathy was defined as Achilles tendon pain in the past medical history. A significant increase in Achilles tendon risk was found. Limited evidence was shown. One low-quality study investigated the effect of less collagen content, less lysyl pyridinoline, less hydroxylysyl pyridinoline, less pentosidine and a lower Young’s modulus (measure of the tendon tissue stiffness) on Achilles tendon rupture risk [34]. No association between less lysyl pyridinoline, less hydroxylysyl pyridinoline and less pentosidine was found. Less collagen content and lower Young’s modulus showed a significantly higher Achilles tendon rupture risk. Young’s modulus was calculated as the linear part of the stress–strain curve. Limited evidence was found. 3.4.2.2 Elements of Tendon Changes One low-quality study assessed the effect of type I collagen and type III collagen on Achilles tendon ruptures [35]. This study reported significantly stronger type I collagen staining in cells from normal Achilles tendons than from ruptured Achilles tendons. The presence of an increased amount of type III collagen had a positive correlation with the Achilles tendon rupture risk. Limited evidence was shown. One high-quality study assessed the effect of the length of fibrils on Achilles tendon ruptures [19]. Decreased fibril size (60–150 nm) increased the Achilles tendon rupture risk. Moderate evidence was found. One low-quality study investigated the effect of collagen fiber diameter on Achilles tendon rupture risk. The average collagen fiber diameter in ruptured tendons was 18.2 ± 1.0 lm versus 28.5 ± 2.7 lm in the control tendons (p \ 0.0001). Limited evidence was found for an association between lower collagen fiber diameter and Achilles tendon rupture risk [36]. One low-quality study evaluated the effect of the anterior–posterior diameter of the Achilles tendon and the tendon rupture risk [37]. The average maximum anterior– posterior diameter of the ruptured tendon was 11.7 mm. The patients’ contralateral tendons measured an average of 5.4 mm and there was an average thickness of 4.9 mm in the controls. A greater anterior to posterior diameter significantly increased the Achilles tendon rupture risk. Limited evidence was found.

One low-quality study assessed the effect of the crimp angle of the collagen fibers on Achilles tendon rupture risk. The ruptured tendons had an average crimp angle of 14.7 ± 2.2 versus an average crimp angle of 16.6 ± 1.0 in the control group (p = 0.003) [36]. Limited evidence was found for lower crimp angle as a risk factor for Achilles tendon rupture. One low-quality study showed limited evidence for an increased Achilles tendon rupture risk and more separation of collagen fibers, increased waviness of collagen fibers, loss of collagen fiber arrangement, decreased number of nuclei in tenocytes, more rounded nuclei in tenocytes, increased cellularity, more vascular bundles, less collagen stainability, and more glycosaminoglycans stainability [38]. 3.4.3 Ankle and Foot Position 3.4.3.1 Underpronating Alignment of Ankle One lowquality study investigated the effect of underpronating alignment of the ankle on Achilles tendon ruptures [39]. A significant increase in Achilles tendon rupture risk was found. Limited evidence was shown. 3.4.3.2 Longitudinal High Arch One low-quality study addressed the effect of longitudinal high arch and Achilles tendon rupture risk [39]. The height of the longitudinal arch was measured with a footprint on a table. A high arch was classified as a footprint broken in the area of the arch; a raised incidence of Achilles tendon ruptures was shown in this group. Limited evidence was found. 3.4.4 Genetic Factors One high-quality study and one low-quality study reported the effect of MMP3 gene expression and Achilles tendon rupture risk [20, 57]. In the study of Raleigh et al., no significant effects were demonstrated [20]. In the study of Jones [57], the presence of MMP3 increased the Achilles tendon rupture risk. Conflicting evidence was found. One low-quality study investigated the presence of MMP1, MMP7, MMP9, MMP11, MMP14, MMP17, MMP19, MMP24, MMP25, MMP28, a disintigrin and metalloproteinase trombospondin motifs (ADAMTS)4, ADAMTS7, ADAMTS13, tissue inhibitor of metalloproteinase (TIMP) 1, TIMP2, TIMP3, TIMP4, a disintigrin and metalloproteinase (ADAM)8, ADAM12, and ADAM17 on the Achilles tendon rupture risk [40]. Limited evidence for an association between the presence of MMP1, MMP7, MMP9, MMP11, MMP14, MMP19, MMP24, MMP25, MMP28, ADAMTS4, ADAMTS7, ADAMTS13, TIMP1, TIMP2, TIMP3, TIMP4, ADAM8, ADAM12, ADAM17 and Achilles tendon rupture risk

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existed. There was limited evidence against an association between the Achilles tendon rupture risk and presence of MMP17. Two low-quality studies calculated the effect of the COL1A1 Sp1-binding site polymorphism on Achilles tendon rupture risk [25, 42]. Limited evidence was found for no association between COL1A1 Sp1-binding site polymorphism and the Achilles tendon rupture risk. Two low-quality studies investigated the effect of vascular endothelial growth factor (VEGF) on Achilles tendon ruptures [41, 42]. In the study of Petersen et al. [41, 42], no association was shown. One low-quality study showed a positive association between VEGF and Achilles tendon rupture [42]. There is consequently conflicting evidence for an association between VEGF and Achilles tendon rupture risk. One low-quality study assessed the effect of higher cyclooxygenase (COX) 2 expression, higher oncostatin M (OSM) expression, higher leukemia inhibitor factor (LIF), higher ciliary neurotrophic factor (CNTF), Higher interleukin (IL) 6 expression and lower IL6 receptor (IL6R) expression on the Achilles tendon rupture risk [42]. Limited evidence was found for higher COX2 expression, higher OSM expression, higher LIF expression, higher IL6 expression and lower IL6R expression increasing the Achilles tendon rupture risk. Limited evidence was shown for an absence of association between Achilles tendon ruptures and higher CNTF expression. Two low-quality studies assessed the effect of ABO blood group distribution on the Achilles tendon rupture risk [43, 44]. One study showed a different ABO blood group distribution in patients with Achilles tendon ruptures compared with the control group (p = 0.030) [43]. A decreased blood group A/O ratio was shown in the Achilles tendon rupture group. One study did not demonstrate a significant association between the ABO blood group distribution and the Achilles tendon rupture risk [44].

In another study, hypercholesterolemia was associated with an increased Achilles tendon rupture risk [22]. Conflicting evidence was found. 3.5.1.3 Sports Activity One low-quality study evaluated the effect of sports activities on Achilles tendon ruptures [45]. No significant association was shown. Sports activities were not specified. One low-quality study assessed the effect of professional sprinting on the Achilles tendon rupture risk. The presence of an Achilles tendon rupture was significantly higher in male former elite sprinters [46]. One low-quality study showed that Achilles tendon ruptures occur significantly more often in recreational sports activities compared with other tendon ruptures [26]. Conflicting evidence was found. 3.5.2 Medication 3.5.2.1 Quinolones Five low-quality studies reported the risk of quinolone use on Achilles tendon ruptures [21–23, 28, 47]. All studies found similar results. A significant increase in Achilles tendon rupture was shown. Limited evidence was found. 3.5.2.2 Other Antibacterials Two low-quality studies reported the effect of antibacterial use, other than fluoroquinolones, and the risk of Achilles tendon rupture [22, 28]. Seeger et al. found no association between the Achilles tendon rupture risk and use of ofloxacin, levofloxacin, ciprofloxacin, azithromycin or clarithromycin [28]. Van der Linden et al. found no association between Achilles tendon rupture and use of tetracycline, amoxicillin, penicillin and macrolides [22]. Both studies reported no increased risk of Achilles tendon rupture while using antibacterials other than fluoroquinolones. Limited evidence was found.

3.5 Modifiable Predictors 3.5.1 Patient Characteristics 3.5.1.1 Obesity Three low-quality studies evaluated the effect of increased body weight on Achilles tendon ruptures [22, 25, 28]. In the studies of Van der Linden et al. and Seeger et al., a BMI [40 kg/m2 increased the Achilles tendon risk [22, 28]. In the study of Posthumus et al., a BMI [25 kg/m2 was a risk factor for Achilles tendon rupture [25]. The three studies showed a significant positive association, resulting in limited evidence. 3.5.1.2 Hypercholesterolemia Two low-quality studies investigated the effect of hypercholesterolemia on Achilles tendon ruptures [22, 31]. In one study, hypercholesterolemia did not affect the risk of Achilles tendon rupture [31].

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3.5.2.3 Corticosteroids Two low-quality studies assessed the association between oral corticosteroid use and Achilles tendon rupture risk [22, 28]. Both studies found a significant increase in risk. Limited evidence was shown. One low-quality study evaluated the association between local corticosteroid injections and Achilles tendon rupture risk [33]. Limited evidence for no association was shown. 3.5.2.4 Salicylates In one low-quality study, the risk of salicylates on Achilles tendon ruptures was investigated [31]. No significant association was found. Limited evidence was shown. 3.5.2.5 Environmental Factors One low-quality study assessed the effect of smoking on Achilles tendon ruptures

Predictors of Achilles Tendon Ruptures

[31]. No significant effects were demonstrated. Limited evidence was found. One low-quality study evaluated the effect of living in urban areas and the Achilles tendon rupture risk [7]. A significant increase in Achilles tendon ruptures was reported. Limited evidence was found. One low-quality study investigated the effect of spring and summer on the Achilles tendon rupture risk [30]. A positive association was found with these seasons. Limited evidence was shown.

4 Discussion This systematic review is the first in this field and aimed to provide an overview of the current evidence for known determinants influencing the risk of Achilles tendon ruptures. Our search strategy yielded 31 relevant studies, of which only two were classified as being of high quality. According to the results of this systematic review, the etiology of Achilles tendon rupture is shown to be multifactorial and includes local factors, biomechanical factors, histological factors, medication and genetic factors. We found moderate evidence for an association between Achilles tendon rupture risk and decreased fibril size. There was limited evidence for an association with BMI above 25 kg/m2 or BMI above 40 kg/m2, male sex, higher age, Black race, oral corticosteroid use, quinolone use, higher COX2 expression, higher OSM expression, higher LIF expression, higher IL6 expression, lower IL6R expression, VEGF expression, more type III collagen, less collagen content, lower Young’s modulus, less type I collagen, higher anterior–posterior diameter of the Achilles tendon, lower diameter of collagen fibers, lower crimp angle of collagen fibers, more separation of collagen fibers, increased waviness of collagen fibers, loss of collagen fiber arrangement, decreased number of nuclei in tenocytes, more rounded nuclei in tenocytes, increased cellularity, more vascular bundles, less collagen stainability and more glycosaminoglycans stainability, MMP1, MMP7, MMP9, MMP11, MMP14, MMP19, MMP24, MMP25, MMP28, ADAMTS4, ADAMTS7, ADAMTS13, TIMP1, TIMP2, TIMP3, TIMP4, ADAM8, ADAM12, ADAM17, living in urban areas, spring and summer season, renal transplants, inflammatory bowel disease, ipsilateral sciatic pain, trauma, autoimmune arthritis, infectious arthritis, rheumatoid arthritis, and previous tendinopathy. Limited evidence for the modifiable factors increased body weight, oral corticosteroid use, quinolone use, and living in an urban area was found. Non-modifiable determinants are elder age, Black race, inflammatory bowel disease, trauma, autoimmune arthritis, infectious arthritis, rheumatoid arthritis, tendinopathy,

more type III collagen, less type I collagen, less collagen content, higher COX2 expression, higher OSM expression, higher LIF expression, higher IL6 expression, lower IL6R expression, VEGF expression, lower Young’s modulus, higher anterior posterior diameter, lower diameter of collagen fibers, lower crimp angle of collagen fibers, more separation of collagen fibers, increased waviness of collagen fibers, loss of collagen fiber arrangement, decreased number of nuclei in tenocytes, more rounded nuclei in tenocytes, increased cellularity, more vascular bundles, less collagen stainability and more glycosaminoglycans stainability, MMP1, MMP7, MMP9, MMP11, MMP14, MMP19, MMP24, MMP25, MMP28, ADAMTS4, ADAMTS7, ADAMTS13, TIMP1, TIMP2, TIMP3, TIMP4, ADAM8, ADAM12, ADAM17, decreased fibril size, general osteoarthritis, tendinitis, Achilles bursitis, enthesopathy, orthopedic visit, podiatry visit, past history of musculoskeletal related disorder, longitudinal high arch, seasonal factors, renal transplantees and ipsilateral sciatic pain and underpronating alignment of ankle. Modifiable determinants are obesity, oral quinolone use, oral corticosteroid use, living in urban areas and hypercholesterolemia. Clinical practitioners may therefore be cautious when prescribing oral quinolone and corticosteroids to prevent an increased Achilles tendon rupture rate. Briefings could make clinical practitioners aware of the problem. Patients with BMI above 25 kg/m2 should aim to lose weight to decrease the Achilles tendon rupture risk [32]. We found a loss of larger fibrils in the core and periphery of the Achilles tendon as a predictor for Achilles tendon rupture. The cross-sectional area of the fibrils was measured using digitized electron microscopy biopsy cross-sections after a tendon rupture. The core of the ruptured Achilles tendons contained significantly fewer fibrils of medium to large size compared with control tissue samples. Theoretically, an increase in fibril size would lead to an increase in mechanical strength. In one article, fibril size was measured by using histograms on the fibril diameter distributions for mature rat tail tendon and direct electron microscope observations [48]. The association between mechanical strength and fibril size in adult human Achilles tendons has not been studied. However, animal studies showed that during development there is an increase in fibril diameter that shows to be synchronized with higher tendon strength [49, 50]. Therefore, a decrease in fibril size may increase the Achilles tendon rupture risk, especially when inactive subjects decide to start higher demanding sport activities. However, we should be aware that this retrospective study design cannot rule out that these findings are a result of the tendon rupture. Furthermore, this invasive technique is not applicable in healthy subjects to

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predict tendon rupture risk, which makes it less valuable in the current clinical setting. A possible explanation for the conflicting evidence for sports activities increasing the Achilles tendon rupture risk could be that sport activities were not specified in the study of Raunest et al. [45]. Moreover, the study population was small [45]. In one low-quality study, professional sprinting increased the Achilles tendon rupture risk [46]. In another study, Achilles tendon ruptures occurred significantly more often in recreational sports activities, compared with other tendon ruptures [26]. Several studies reported that the sports with the highest percentage of Achilles tendon rupture were those that involved running and jumping [9, 26]. In the scientific literature, use of quinolones, corticosteroids, hypercholesterolemia, men with higher age and increased physical activity are frequently mentioned as risk factors for Achilles tendon rupture [51]. However, we found only limited evidence for these determinants. The mechanisms behind the quinolone effect on Achilles tendon rupture are not well understood. Shakibaei et al. [52] hypothesized that quinolones exert their effects on Achilles tendons by disturbing the interaction between cells and matrix by chelating divalent ions. Quinolones may interact with regulating proteins of tenocytes and cause damage to the Achilles tendon structure. Two studies reported the presence of necrosis and neovascularization without inflammation in ruptured Achilles tendons [53, 54]. Quinolone-induced apoptosis at the last stage of the process has been suggested recently [55]. In two low-quality studies, limited evidence for oral corticosteroid use increasing Achilles tendon rupture risk was shown [22, 28]. Animal studies showed that corticosteroid injections in tendons should be avoided, but the true incidence of tendon ruptures after local corticosteroid injections is unknown. In the literature, many case reports showed Achilles tendon rupture after use of corticosteroid injections, but only one low-quality case–control study was performed on the effect of local corticosteroid injections on Achilles tendon rupture risk [56, 57]. The higher incidence of Achilles tendon ruptures in higher age could possibly be explained by degenerative changes, by prolonged stress on the Achilles tendon, and possibly by decreased fibril size of the tendon [19]. It is unknown whether confounding factors, like increased comorbidities, medication use, increased serum lipids and decreased regular activity level may play a role in the elderly. A potential reason for men having an increased risk of Achilles tendon ruptures could be that men in general have greater muscle mass and are able to generate greater force of contraction. Therefore, they could be more likely to have

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degenerative tendons as a result of repeated tendon stress. In the study of Vosseller et al. [29], no association between men and Achilles tendon risk was found. A potential reason could be that the study was based on a chart review. Therefore misclassification could be possible. A possible explanation for conflicting evidence of the influence of hypercholesterolemia on Achilles tendon ruptures is the small number of people used in the study by Kraemer et al. [31]. We included studies that consisted of at least ten adult patients with Achilles tendon rupture. However, in this study a type II error might be responsible for the findings. In one study, a difference was shown between ABO blood groups in patients with an Achilles tendon rupture compared with healthy controls [43]. A higher Achilles tendon rupture incidence was found in individuals with blood group O. A possible explanation could be a genetic linkage [43]. However, no collagen genes are located in chromosome 9, while the ABO blood group gene is located there [58]. One study did not show an association between ABO blood group distributions and Achilles tendon ruptures [44]. An explanation for the conflicting evidence could be the differences in ABO blood group distribution between populations. Conflicting evidence was found for MMP3 expression associated with Achilles tendon rupture risk. Jones included only 12 Achilles tendon rupture patients. MMPs are involved in the remodeling of extracellular matrix, because of their proteolytic capabilities [59]. TIMPs inhibit the activity of MMPs. Consequently, an imbalance between the activities of MMPs and TIMPs can alter the collagen production in tendons [60]. We found conflicting evidence for an association between VEGF levels and the Achilles tendon rupture risk [41, 42]. VEGF is a potent stimulator of neovascularization, which has previously been identified in patients after Achilles tendon rupture [61]. Studies showed that the IL6 and COX2 expression increased with mechanical strain [62]. This could be an explanation for the high levels of IL6 and COX2 in Achilles tendon ruptures. The lower IL6R levels could be a response to high IL6 levels. A study showed that OSM, CNTF, and LIF suppressed the synthesis of proteoglycans in articular cartilage [63]. This process could be similar in the Achilles tendon. There were several weaknesses in the included studies of the systematic review. Because of heterogeneity of several study aspects, no meta-analysis could be performed. We provided an alternative by performing a bestevidence synthesis. We assessed the methodological quality of all studies using modified questions from existing quality assessment tools [15–17]. The review is mainly based on cross-sectional data and therefore the strength of

Predictors of Achilles Tendon Ruptures

evidence is limited by the quality of the available studies. Only five studies were cohort studies, but none of them were prospective. Several quality criteria were not clearly described; specifically, information on potential bias (e.g., inclusion bias), handling of missing data and reasons for dropout was lacking in most studies. In most studies, informed consent status was described but the inclusion and exclusion criteria were not clear, therefore inclusion bias may be possible. The histological findings described in our review are retrospective and cause–effect relations are not certain. Only 17 of the 31 studies (54.8 %) corrected for confounders [10, 19–23, 25, 27, 28, 31, 35, 37, 46, 47]. Consequently, the reported influence of determinants on the development of Achilles tendon ruptures may be partly explained by other factors. Another weakness might be the population size in the included studies. Only fourteen (14 %) studies included more than 100 people [7, 10, 21–23, 26–30, 32, 39, 46, 47]. The other studies were relatively small and might, therefore, have been underpowered to allow firm conclusions. Another limitation might be that we included registerbased studies. In daily clinical practice, adverse side effects are not always reported, thereby potentially leading to an underestimation of the risk-factor contribution. Verification bias might have been present in several studies. The diagnostic test for the determinant was not the same in patients and controls. The test results could have influenced the choice of the reference standard. Future studies on the determinants predicting Achilles tendon rupture should ideally be prospective with large patient numbers and use diagnostic tests that are the same for patients and healthy controls. Because it will be very challenging to apply a prospective design, a case–control study could also sufficiently answer questions in this field. In that case, correction for potential confounders is needed in the statistical analysis. 5 Conclusions In conclusion, based on the results of this systematic review, there is moderate evidence for an association between a decreased fibril size and Achilles tendon rupture risk. There is limited evidence for many other factors, like higher weight, living in an urban area, oral quinolone and corticosteroid use as modifiable factors. These factors may be of interest in future intervention studies. These results also showed that more well designed, large, prospective studies are needed to evaluate the determinants influencing the risk of Achilles tendon rupture. Acknowledgment The authors thank G.B. de Jonge and W. Bramer, medical librarians of the Erasmus Medical Center in Erasmus MC, for assistance in performing the literature search.

No sources of funding were used to assist in the preparation of this review. The authors have no potential conflicts of interest that are directly relevant to the content of this review. Contributions Femke Claessen, Duncan Meuffels, and Robert-Jan de Vos contributed to the conception and design of the study and to interpretation of the data. Femke Claessen drafted the article. Duncan Meuffels, Max Reijman and Robert-Jan de Vos revised the article for important intellectual comment. All authors gave final approval of the version to be submitted.

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