Is adiposity an under-recognized risk factor for tendinopathy A systematic review.код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 61, No. 6, June 15, 2009, pp 840 – 849 DOI 10.1002/art.24518 © 2009, American College of Rheumatology ORIGINAL ARTICLE Is Adiposity an Under-Recognized Risk Factor for Tendinopathy? A Systematic Review JAMES E. GAIDA,1 MAUREEN C. ASHE,2 SHONA L. BASS,1 AND JILL L. COOK1 Objective. Tendon injuries have been reported to occur more frequently in individuals with increased adiposity. Treatment also appears to have poorer outcomes among these individuals. Our objective was to examine the extent and consistency of associations between adiposity and tendinopathy. Methods. A systematic review of observational studies was conducted. Eight electronic databases were searched (Allied and Complementary Medicine, Biological Abstracts, CINAHL, Current Contents, EMBase, Medline, SPORTDiscus, and Web of Science) and citation tracking was performed on included reports. Studies were included if they compared adiposity between subjects with and without tendon injury or examined adiposity as a predictor of conservative treatment success. Results. Four longitudinal cohorts, 14 cross-sectional studies, 8 case– control studies, and 2 interventional studies (28 in total) met the inclusion criteria, providing a total of 19,949 individuals. Forty-two subpopulations were identiﬁed, 18 of which showed elevated adiposity to be associated with tendon injury (43%). Sensitivity analyses indicated a clustering of positive ﬁndings among studies that included clinical patients (81% positive) and among case– control studies (77% positive). Conclusion. Elevated adiposity is frequently associated with tendon injury. Published reports suggest that elevated adiposity is a risk factor for tendon injury, although this association appears to vary depending on aspects of study design and measurement. Adiposity is of particular interest in tendon research because, unlike a number of other reported risk factors for tendon injury, it is somewhat preventable and modiﬁable. Further research is required to determine if reducing adiposity will reduce the risk of tendon injury or improve the results of treatment. INTRODUCTION Increased adiposity is a well-recognized risk factor for many diseases, including cardiovascular disease (CVD) (1), chronic kidney disease (2), and type 2 diabetes mellitus (DM) (3). It is only recently that musculoskeletal manifestations of adiposity have been acknowledged. Musculoskeletal problems associated with increased adiposity are often attributed to increased mechanical loading, but some authors suggest that this may be overly simplistic (4). One particular type of musculoskeletal symptom, tendon injury, is increasingly recognized as a major cause of morbidity in the work force (5), as well as in active (6) and inactive people (7). Whether or not increased adiposity is 1 James E. Gaida, BPhysio(Hons), Shona L. Bass, PhD, MSc, BSc, Jill L. Cook, PhD, BAppSci(Phty): School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Victoria, Australia; 2Maureen C. Ashe, PhD, MSc, BSc(PT): School of Rehabilitation Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Address correspondence to James E. Gaida, BPhysio(Hons), Deakin University, 221 Burwood Highway, Melbourne, Victoria, 3125, Australia. E-mail: email@example.com. Submitted for publication July 2, 2008; accepted in revised form February 17, 2009. 840 associated with tendon injury has received very little research attention. Clinical texts have not yet reported increased adiposity (or obesity) as a risk factor for tendon injury. There is a growing body of evidence showing that increased adiposity (referred to as obesity in pronounced cases) promotes a chronic low-grade microvascular inﬂammation, and this mechanism underpins the wellknown associations with CVD, chronic kidney disease, and type 2 DM (8,9). Similar systemic mechanisms may also contribute to musculoskeletal symptoms that develop in the presence of increased adiposity, tendon pain (tendinopathy) and tendon rupture potentially being 2 such injuries. Tendon injury is a problem that causes substantial morbidity in a broad cross-section of populations. Cross-sectional data suggest that individuals with tendon injury have either higher adiposity levels (10,11) or distribute adipose tissue around the body in a different manner (12,13), whereas intervention data suggest that treatment for tendinopathy may be less effective among patients with high adiposity levels (14). In addition, elevated adiposity is associated with high cytokine levels (8,9), and several mechanisms exist whereby elevated cytokine levels may Association of Elevated Adiposity and Risk of Tendinopathy either directly or indirectly affect tendon structure (15). These reports, and a background of increasing adiposity levels in the community, led us to perform a systematic review examining these associations. MATERIALS AND METHODS A systematic review aims to comprehensively compile and synthesize evidence to answer an explicit research question using reproducible methods, and is often applied to randomized controlled trials. However, when the question of interest concerns etiology, randomized controlled trials are not only problematic to implement, they are often unethical (16). The study of etiology is therefore typically conducted using observational designs such as cross-sectional studies, case– control studies, or cohort studies, with systematic reviews increasingly being used to summarize these results (16). This systematic review of observational studies asks the question, “Is elevated general or regional adiposity related to tendon injury?” Our outcomes of interest were 1) a clinical diagnosis of tendinopathy or tendon rupture and 2) abnormal tendon imaging on ultrasound or magnetic resonance imaging (MRI). The exposures of interest were 1) increased overall adiposity and 2) altered body fat distribution. Populationbased studies typically use body mass index (BMI) to measure adiposity, and the World Health Organization deﬁnes overweight as a BMI between 25.0 and 29.9 kg/m2 and obesity as a BMI of ⱖ30 kg/m2 (17). Anthropometric measures such as waist circumference and waist to hip ratio are often used to quantify body fat distribution. Body composition can also be quantiﬁed using imaging methods. Modalities that distinguish fat from bone and lean tissue include MRI, computed tomography (CT), and dual x-ray absorptiometry (DXA). For reasons of expense, time, access, and radiation exposure (CT and DXA), these techniques are often limited to smaller studies. For clarity, we used adiposity throughout this report to describe increased adiposity or altered body fat distribution measured by any of these methods. Identiﬁcation and selection of the studies. One author (JEG) conducted an electronic literature search in March 2007 using multiple databases (Allied and Complementary Medicine [1985 to March 2007], Biological Abstracts [1985 to February 2007], CINAHL [1982 to March week 1, 2007], Current Contents [week 27, 1993 to week 12, 2007], EMBase [1988 to week 10, 2007], Medline [1950 to February week 4, 2007], SPORTDiscus [1830 to November 2006], and Web of Science [1945 to March 13, 2007]) to identify studies examining associations between adiposity and tendon injury in humans. No limitation was applied regarding publication year, although only studies published in English were considered. The medical subject headings used included Tendons, Tendon Injuries, Tendinopathy, Tendinitis, Adiposity, Obesity, Body Mass Index, Anthropometry, Body Fat Distribution, and Adipose Tissue. Plain text searching was also used in combination with wildcards and truncation (18). Terms used for plain text searching included tend#nopath$, tend#nos#s, achil?o- 841 dynia, obesity, adiposity, body composition, fat distribution, anthropometry, waist circumference, hip circumference, (waist adj2 hip) AND ratio, (abdominal OR visceral) adj5 adipose (for full details, see Supplemental Appendix A, available in the online version of this article at http:// www3.interscience.wiley.com/journal/77005015/home). Electronic searches with broad scope (tendon AND obesity, tendon AND body composition, tendon AND adiposity) were conducted using the Google and Google Scholar search engines. The ﬁrst 200 records for each search were screened for relevance by title. Hand searching supplemented the electronic searches. Two authors (JEG, JLC) independently searched the reference lists of included articles for relevant studies. Additionally, 5 articles considered to be of key relevance (10,11,13,14,19) were identiﬁed on PubMed and the “Related Articles” function was selected. Both authors independently assessed the ﬁrst 100 citations linked to each of the 5 key articles. Records were imported into Endnote, version 9.0.0 for Macintosh (Thompson, Stamford, CT). Letters, conference proceedings, and duplicates were excluded. Two authors (JEG, JLC) then independently applied the predeﬁned inclusion criteria to the titles and abstracts of the retrieved references. If both authors included the study or if there was disagreement, the full-text article was obtained and checked for eligibility. Disagreement regarding inclusion was resolved by discussion between the 2 authors. To ensure the validity of the included data, only full and original articles from peer-reviewed journals were considered for inclusion. To be eligible, a study had to compare adiposity between individuals with and without tendon injury or examine the inﬂuence of adiposity on recovery from tendon injury. In both cases, the statistical methods had to be appropriate to the study design. Factors predicting successful outcome after surgical intervention for tendon injuries were excluded. Studies examining conservative management of tendon injury, however, were included if treatment was standardized. Carpal tunnel syndrome was excluded a priori because it differs from other tendon injuries in several fundamental aspects. Appropriate assessment of adiposity was considered to include height to weight ratios (e.g., BMI), waist circumference, waist to hip ratio, and adipose tissue volumes or crosssectional areas as measured by CT, MRI, or DXA. Reporting body weight without adjusting for height is not a valid measure of adiposity and these studies were excluded. The published version of each study was examined for methodologic quality using the checklist by Downs and Black (20). Two items suggested by the Centre for Reviews and Dissemination (21) were added. Two authors (JEG, MCA) marked each study, with a third author (JLC) making the ﬁnal decision in the case of disagreement. Data were extracted from each eligible study by 2 of the authors (JEG, MCA). The items were chosen for their ability to highlight the important aspects of study design, the demographics of the studied population, and the deﬁnition of disease. The methods used to measure adiposity were noted, as was the use of cutoffs (e.g., BMI ⬎30 kg/ m2). The association between adiposity and tendon injury was either recorded as an odds ratio or as an effect size 842 (22), and the P value was recorded as calculated from presented data (23). In circumstances where it was not possible to extract these data from the published manuscript, corresponding authors were contacted for the required information. Nine of the 14 corresponding authors contacted supplied the requested data, 2 stated that the data were no longer available, 2 responded but did not provide the requested data, and one author could not be contacted. In one case, all data were available except for the SD of BMI in the tendinopathy group (24). To allow interpretation, a conservative estimate (mean ⫹ 2 SDs) was calculated from the reported SD of BMI in the other studies. If more than one data point was missing, no values were substituted. Because a single study may often report results for multiple groups (e.g., men with upper extremity tendinopathy, women with upper extremity tendinopathy, men with lower extremity tendinopathy, etc.), it was considered important to maintain these subpopulations for the purposes of this review. In contrast, where studies used multiple measures of adiposity (e.g., BMI, waist circumference, and waist to hip ratio) or examined the effect of different cutoffs (e.g., BMI ⬎30 kg/m2 versus BMI ⬎35 kg/m2) to report the results from a single subpopulation, it was important that these results were grouped together and only counted once. Similarly, where data for individuals with unilateral and bilateral tendinopathy were reported separately, online tools were used to combine the 2 groups (25). These tools allowed the input of means and SDs from 2 groups and then calculated the mean and SD of the 2 groups combined. This was performed for the variables of interest (i.e., age, BMI, waist circumference, and waist to hip ratio). Any person participating in an included study was referred to as an individual. This term was further qualiﬁed according to whether they were an individual with a tendon injury (tendinopathy group) or an individual without a tendon injury (control group). Individuals recruited through their participation in organized sports were referred to as athletes, whereas those recruited through their place of employment were known as workers. Finally, those presenting to their health care practitioner for the management of tendon pain were referred to as patients. Of note is that athletes and workers (and those in the general community) often do not seek treatment for tendon pain and so, for example, a group of workers with tendon injuries was not always synonymous with a clinical patient group. Statistical analysis. Where a study showed that individuals with a tendon injury had signiﬁcantly greater levels of adiposity than controls, it was reported as a signiﬁcant positive association. This term was also used when individuals had signiﬁcantly greater abdominal adiposity (deﬁned by elevated waist circumference or waist to hip ratio), because this distribution pattern is associated with increased incidence of CVD, chronic kidney disease, and type 2 DM (9). Conversely, when the opposite was shown (decreased general or abdominal adiposity), it was described as a signiﬁcant negative association. Sensitivity analyses were conducted based on 6 vari- Gaida et al Figure 1. Flow chart describing the source of included articles. BMI ⫽ body mass index. ables: sex (men, women, combined), population (athletes, patients, workers), injury location (upper extremity, lower extremity, not speciﬁed), adiposity measure (BMI, circumferences, other), study design (longitudinal, cross-sectional, case– control), and quality score (above middle rank, below middle rank). The effect of each of these grouping scenarios was tested with a chi-square test (SPSS, version 15.0.1 for Windows; SPSS, Chicago, IL). P values less than 0.05 were considered signiﬁcant. RESULTS A total of 245 unique records were retrieved using the citation databases. The application of inclusion criteria to abstracts reduced the count to 47. Of the 47 potentially applicable studies, 29 were excluded (for full details, see Supplemental Appendix B, available in the online version of this article at http://www3.interscience.wiley.com/journal/77005015/home). Therefore, 18 articles met the inclusion criteria and were included in the review (10 –12,14, 19,24,26 –37) (Figure 1). Citation tracking of these 18 articles yielded a further 6 unique records meeting the inclusion criteria (38 – 43), tracking related articles using PubMed yielded 2 (44,45), and contact with a tendinopathy expert (JLC) yielded an Association of Elevated Adiposity and Risk of Tendinopathy additional 2 (13,46). Using all of the reference tracking techniques described, 28 original research reports meeting the inclusion criteria were identiﬁed (Figure 1) and subsequently marked using the quality criteria. The included studies had a combined total of 9,536 male individuals and 10,413 female individuals. Nineteen points were available from the 18 questions on the quality assessment (one question is marked between 0 and 2). Included studies scored 18 (n ⫽ 5), 17 (n ⫽ 11), 16 (n ⫽ 6), 15 (n ⫽ 2), 13 (n ⫽ 1), 12 (n ⫽ 2), and 10 (n ⫽ 1) out of 19. No studies were excluded on quality assessment. Most points were deducted for an inadequate description of potential confounding variables (n ⫽ 24; deduction of 1 or 2 points from each study), outcome assessors not blinded to exposure (n ⫽ 19), failure to demonstrate that the recruited population was comparable with the source population (n ⫽ 9), non-precise reporting of P values (n ⫽ 8), poorly described aim/hypothesis/objective of the study (n ⫽ 3), failure to report estimates of random variability (n ⫽ 3), cases and controls not recruited from the same population (n ⫽ 3), and cases and controls not recruited over the same time period (n ⫽ 3). Points were also lost for an inadequate description of patient characteristics (n ⫽ 2), inappropriate use of statistical techniques (n ⫽ 2), a lack of an explicit case deﬁnition (n ⫽ 1), and failure to establish accurate outcome measures (n ⫽ 1). Six studies utilized a longitudinal cohort design to investigate risk factors for tendon injury. In 2 of these studies, followup data were not sufﬁciently detailed to allow analysis (26,38). Therefore, only baseline data from these 2 studies were included, and consequently the research is best described as cross-sectional for the purposes of this review. Including these 2 cases, the cross-sectional design was used 14 times. Eight studies were of case– control design, while 2 interventional studies examined BMI as a factor predicting treatment success. Fourteen (50%) of the 28 included studies showed ⱖ1 signiﬁcant positive association between increased adiposity and tendon injury (10 –14,24,26,30,31,34,36,37,44,46). Interestingly, one of these 14 studies (24) identiﬁed a signiﬁcant negative association in one subgroup (female runners with patellar tendinopathy), whereas all other subgroups in the study showed positive associations. The remaining 14 studies found no signiﬁcant association between adiposity and tendinopathy (19,27–29,32,33,35,38 – 43,45). Examination of the subpopulations (rather than the studies as a whole) showed similar results: 18 positive (43%), 23 no association, and 1 negative (Table 1). Effect sizes (Figure 2) were not calculated if odds ratios (Figure 3) were reported in the article. Sensitivity analysis showed no deviation from chisquare distribution for groupings based on sex (2 ⫽ 0.257, 2 df, P ⫽ 0.879), location of injury (2 ⫽ 2.964, 2 df, P ⫽ 0.227), adiposity measure (2 ⫽ 1.667, 2 df, P ⫽ 0.432), or quality score (2 ⫽ 0.138, 1 df, P ⫽ 0.710). When grouped according to the population studied (athletes versus patients versus workers: 2 ⫽ 9.051, 2 df, P ⫽ 0.011) and the study design (longitudinal versus cross-sectional versus case– control: 2 ⫽ 9.365, 2 df, P ⫽ 0.009), the distribution of positive ﬁndings (compare negative and nonsigniﬁcant combined) differed from that expected. A high proportion 843 of positive ﬁndings was noted for patients (13 [81%] of 16) and case– control studies (10 [77%] of 13). Importantly, there was no difference in the frequency of signiﬁcant results when comparing studies falling above and below the median quality score rank. This suggests that elevated adiposity in the study group did not affect the decision to publish to a greater or lesser extent in the articles with a lower quality score. This ﬁnding is an indication that the pool of studies may not be affected by publication bias. This is consistent with the observation that only a small proportion of the included investigations identiﬁed adiposity as a key factor of interest, and as such, this factor would not be expected to affect the decision to publish. DISCUSSION To our knowledge, this is the ﬁrst time a systematic review has examined the association between tendon injury and adiposity. The results show that individuals with tendon abnormality, tendon pain, tendon rupture, or failure to respond to conservative management have signiﬁcantly higher adiposity levels than their respective controls nearly half of the time. This review suggests that individuals with tendinopathy often have higher adiposity, because adiposity is an intrinsic risk factor for this condition. The mechanism linking adiposity and tendinopathy may be mechanical or systemic. The mechanical hypothesis is that weight-bearing tendons are exposed to higher loads with increasing adiposity, and the higher loads then lead to tendinopathy. Studies that report associations between lower extremity tendinopathy and BMI could support this hypothesis. The systemic hypothesis maintains that bioactive peptides released by adipose tissue may inﬂuence tendon structure (direct mechanism). Alternately, systemic metabolic alterations associated with elevated adiposity may affect tendon structure (indirect mechanism). Many of the studies in this review support the systemic hypothesis. Recent work has demonstrated a strong association between tendon abnormality and abdominal adiposity in male athletes (13). In this study, the athlete’s waist circumference was able to discriminate normal from abnormal tendons, whereas body weight, match schedule, and training volume did not. These elite volleyball players had full match and training schedules and thus did not have an opportunity to increase their level of adiposity secondary to a reduction in physical activity. However, longitudinal data are required to conﬁrm that tendon injury develops secondary to elevated adiposity. Additional support for a systemic mechanism comes from the sensitivity analysis, which highlighted equivalent distributions of positive and negative ﬁndings according to whether the affected tendon was in the upper or lower extremity. Because only the tendons of the lower extremity are weight bearing, this ﬁnding supports the earlier suggestion that the association between adiposity and tendinopathy cannot be adequately explained by increased tendon loading. That is, if adiposity increases the risk of tendinopathy predominantly through loading, a 10 12 15 13 US US Sweden France Holmes et al, 1991 (40) Holmes and Mann, 1992 (31) Jacobsson et al, 1992 (32) Leclerc et al, 2001 (41) 12 US Holmes and Lin, 2006 (30) 15 16 Sweden Australia 17 Sweden Gaida et al, 2004 (12)** 16 Sweden Fahlström et al, 2002 (28) Fahlström et al, 2002 (29) Fahlström et al, 2003 (14) 16 17 Australia France 17 Denmark Quality Country score Descatha et al, 2003 (38) Bonde et al, 2003 (26) Cook et al, 2004 (27)** Author, year (ref.) General population Workers Patients Patients Patients Sporting Patients Sporting Sporting Workers Industrial workers Sporting Population Crosssectional Cohort Retrospective case–control Case–control Retrospective case–control Crosssectional Crosssectional Crosssectional Intervention Crosssectional Crosssectional Crosssectional Study design Symptomatic Symptomatic Rupture Rupture Symptomatic Imaging Treatment response Symptomatic Symptomatic Symptomatic Imaging Symptomatic Case deﬁnition Unable to determine Unable to determine Unable to determine Waist†† WHR†† DXA¶¶ BMI ⬎30 BMI ⬎30 37.9 ⫾ 11.6 21 ⫾ 3.1 178:420 178:420 Wrist 254:248 16:51 39:19 BMI ⬎27 (men), ⬎26.5 (women)†† Increased BMI ⱖ2†† BMI ⬎27 (men), ⬎26.5 (women)†† Increased BMI ⱖ2†† 37.7 ⫾ 8.3 (20–59) 37.7 ⫾ 8.3 (20–59) BMI 20% over ideal 57.19 ⫾ 12.98 (19–87) 50–70 20% over ideal 41 51.3 (34–72) BMI 46.1 ⫾ 9.5 0:44 Small†† Negligible†† Unable to determine BMI 44.2 ⫾ 5.9 49.5 (27–77) Negligible†† BMI 23.4 ⫾ 4.3 2.2 (0.92–5.26)†† Unknown†† Unable to determine†† Unable to determine†† For†† Unknown†† Unknown†† Against For¶ Unknown For¶ For§§ Nil†† For¶ Against†† For¶ For¶ Against Against Against Against For For¶ Direction of effect Unable to determine†† Negligible Medium Medium Small Medium 0.89 (0.40–1.98) BMI ⬎27 (men), ⬎26.5 (women) BMI Medium Small Skinfolds 16.6 ⫾ 1.1 (14–18) 16.3 ⫾ 1.0 (14–18) 38.1 ⫾ 9.3 (20–66) Medium Effect size or OR (95% CI)§ Skinfolds BMI Measure of adiposity‡ 38 ⫾ 10.7 Age, years† 38:0 Lateral elbow Unspeciﬁed Posterior tibial Achilles Achilles 25:6 Distal Achilles Patellar 0:39 68:33 25:7 41:25 419:1,338 0:64 71:0 1,291:1,782 Sex, men: women Mid-Achilles Mid-Achilles Mid-Achilles Medial elbow Patellar Shoulder Injury location Table 1. Summary of results from individual studies* (continued) ⬍ 0.15†† ⬎ 0.15†† ⬎ 0.15†† ⬎ 0.15†† 0.681# 0.005 ⬎ 0.05 ⬍ 0.001 ⬍ 0.05†† 0.5591‡‡ ⬍ 0.001 0.1597‡‡ ⬍ 0.05 ⬍ 0.01 0.4804# 0.1197# 0.1748# 0.0795# 0.0001# P 844 Gaida et al Tanaka et al, 2001 (45) Sayana and Maffulli, 2007 (35) Seeger et al, 2006 (36) Shiri et al, 2006 (37) 17 Finland 18 18 US US 16 16 US UK Workers 18 Workers Workers Patients Patients Workers Patients Workers 17 Mokone et al, 2005 (34) Ono et al, 1998 (42) Ritz, 1995 (43) 17 Workers Sporting Military Population South Africa Japan Finland Miranda et al, 2005 (33) 17 17 Australia France 18 Belgium Quality Country score Melchior et al, 2006 (44) Mahieu et al, 2006 (19) Malliaras et al, 2007 (13)** Author, year (ref.) Crosssectional Crosssectional Case–control Crosssectional Crosssectional Intervention Case–control Crosssectional Crosssectional Crosssectional Cohort Study design Symptomatic Symptomatic Rupture Treatment response Symptomatic 0.90 (0.57–1.42) 1.42 (0.85–2.39) 1.01 (0.56–1.81) Small BMI ⬎30 BMI ⬎30 Shoulder BMI ⬎30 BMI 3.5 (1.6–7.5)†† 1.9 (1.0–3.7)†† 1.4 (0.8–2.4)†† 1.2 (0.7–2.1)†† 1.3 (0.8–2.2)†† 1.16 (0.77–1.76) WHR ⬎0.95†† BMI ⬎30†† Waist ⬎100†† WHR ⬎0.95†† BMI ⬎30†† BMI ⬎25 46.3 ⫾ 9.6 (30–64) 2.3 (1.1–4.7)†† Waist ⬎100†† 46.3 ⫾ 9.6 (30–64) 2.0 (1.2–3.1) Obesity (ICD-9) 40.5 ⫾ 5.0 Negligible 1.0 (0.9–1.1) Large BMI Ponderal index BMI BMI 47.3 ⫾ 23.7 (20–76) 49.6 ⫾ 4.6 (40–59) 46.2 (18–64) 44.7 ⫾ 8.4 (30–64) 44.2 ⫾ 8.8 (30–64) 40.1 ⫾ 12.0 14,647:15,427 18 to ⱖ65 2,245:2,453 Lateral elbow Distal upper extremity 2,245:2,453 692:255 18:16 290:0 Medial elbow Achilles Achilles Elbow 0:575 163:78 0:1,795 0:1,107 1,945:0 38 ⫾ 10.3 (18–59) Small Medium†† Medium†† 1.56 (1.07–2.27) WHR†† BMI†† BMI 30 26.1 ⫾ 5.3 (19–43) 0:40 BMI Large†† Large†† Small†† WHR†† BMI†† Waist†† 38 ⫾ 10.3 (18–59) Very large†† Waist†† 26.1 ⫾ 5.3 (19–43) 69:0 Medium Effect size or OR (95% CI)§ 73:0 Measure of adiposity‡ BMI Age, years† 18.40 ⫾ 1.29 Sex, men: women 6 upper 1,549:0 extremity diagnoses## 0:1,107 Shoulder 1,549:0 Patellar Achilles Injury location Symptomatic/ Achilles rupture Symptomatic Elbow Symptomatic Symptomatic Imaging Symptomatic Case deﬁnition Table 1. (Cont’d) For†† For†† For For§§ For§§ For†† For§§ For¶ Against Unknown Nil For¶ For Nil For Against For For†† For†† For¶ For§§ For§§ For†† For§§ For Direction of effect (continued) 0.7551# ⬎ 0.05 ⬍ 0.001 ⬎ 0.2 ⬎ 0.2 0.48†† 0.09†† ⬍ 0.01†† ⬍ 0.01†† 0.13†† ⬍ 0.01†† 0.083 P Association of Elevated Adiposity and Risk of Tendinopathy 845 17 US Industrial workers Patients Patients Patients Patients Population Cohort Cohort Case–control Case–control Retrospective case–control Study design Patellar Achilles Injury location Symptomatic Symptomatic Upper extremity Medial or lateral elbow Symptomatic/ Patellar imaging Surgery Shoulder Symptomatic Case deﬁnition 27:18 48 38.1 ⫾ 7.8 65.1 ⫾ 6.3 (55–74) 0:154 100:252 64.5 ⫾ 6.0 (55–74) 26.0 ⫾ 6.8 0:1,076 926:0 0:1,076 42:21 157:0 36.2 ⫾ 4.75 Age, years† 926:0 Sex, men: women BMI BMI ⬎30 BMI ⱖ35†† BMI 30–34.9†† BMI ⱖ35†† BMI 30–34.9†† BMI BMI BMI BMI BMI Measure of adiposity‡ Unable to determine 1.86 (1.07–3.22)†† 3.13 (1.29–7.61)†† 2.43 (1.39–4.22)†† 3.51 (1.80–6.85)†† 1.93 (1.12–3.34) Large Negligible Very large Medium Large Effect size or OR (95% CI)§ For For¶ For§§ For§§ For§§ For§§ For¶ For Against¶ For¶ For¶ Direction of effect 0.07¶¶¶ 0.018§§§ ⬍ 0.0001*** 0.3814††† ⬍ 0.0001*** 0.0047‡‡‡ ⬍ 0.0001*** P * OR ⫽ odds ratio; 95% CI ⫽ 95% conﬁdence interval; BMI ⫽ body mass index; WHR ⫽ waist to hip ratio; DXA ⫽ dual x-ray absorptiometry; ICD-9 ⫽ International Classiﬁcation of Diseases, Ninth Revision. † Values are the mean ⫾ SD, mean ⫾ SD (range), mean (range), mean, or range. ‡ BMI is measured in kg/m2. § Effect size calculated according to Hedges’ modiﬁcation of Cohen’s d (also known as Hedges’ g) (22). ¶ Signiﬁcant at P ⬍ 0.05. # Calculated from provided data. ** Unilateral, bilateral, and tendinopathy groups combined for calculation of effect size. †† Grouping where multiple outcome measures are used on the same subpopulation (see Materials and Methods for details). ‡‡ Calculated from provided data. Grouping where multiple outcome measures are used on the same subpopulation (see Materials and Methods for details). §§ Signiﬁcant at P ⬍ 0.05. Grouping where multiple outcome measures are used on the same subpopulation (see Materials and Methods for details). ¶¶ Trunk fat. Grouping where multiple outcome measures are used on the same subpopulation (see Materials and Methods for details). ## Six principal diagnoses: rotator cuff syndrome, epicondylitis, cubital tunnel syndrome, extensor/ﬂexor tendonitis/tenosynovitis, de Quervain’s disease, and carpal tunnel syndrome. *** Calculated from provided data. Factor was not retained in multiple logistic regression analysis. SD of BMI in the injured group was estimated (mean ⫹ 2 SDs) using a comparable measure across the other studies. ††† Calculated from provided data. SD of BMI in the injured group was estimated (mean ⫹ 2 SDs) using a comparable measure across the other studies. ‡‡‡ Calculated from provided data. Factor was not retained in multiple logistic regression analysis. §§§ Groups were compared with t-test in addition to logistic regression. ¶¶¶ Factor was not retained in multiple logistic regression analysis. 16 US 17 US et al, (11) et al, (39) 18 Australia Warden et al, 2007 (46) Wendelboe et al, 2004 (10) Werner 2005 Werner 2005 17 Canada Quality Country score Taunton et al, 2002 (24) Author, year (ref.) Table 1. (Cont’d) 846 Gaida et al Association of Elevated Adiposity and Risk of Tendinopathy 847 Figure 2. Effect sizes (Hedges’ modiﬁcation of Cohen’s d) for increased adiposity in the group with tendon injury (or failure to respond to conservative treatment). Positive scores indicate increased adiposity. * Signiﬁcant at P ⬍ 0.05. WC ⫽ waist circumference; WHR ⫽ waist to hip ratio; DXA ⫽ dual x-ray absorptiometry; BMI ⫽ body mass index. characteristic nature that is diagnosed as arising from a tendon may in fact be due to another structure with a similar innervation pattern. Future investigations would ideally conﬁrm the clinical diagnosis of tendinopathy with appropriate imaging and/or histopathology, where available. Although the evidence linking adiposity and tendinopathy is not conclusive, unlike some other putative risk factors (i.e., gene polymorphisms , prior history of tendon rupture , sex, and age), elevated adiposity is somewhat preventable and reversible (other modiﬁable risk factors include medication exposure [ﬂuoroquinolone antibiotics (48), statins (49)] and unaccustomed, repetitive tendon loading). If evidence in favor of this hypothesis continues to accumulate, and cause and effect are established with longitudinal data, the next step will be to determine how these factors are linked and through which biologic pathways they act (50). stronger association would be expected in the tendons of the lower extremity in comparison with the tendons of the upper extremity. Some measures of adiposity also support the systemic hypothesis. Although waist circumference and waist to hip ratio cannot differentiate between lean and fat tissue, they are considered valid surrogates of visceral adipose tissue volume (waist circumference) and the ratio of central to peripheral fat storage (waist to hip ratio). A central distribution of fat (large waist circumference) increases the risk of CVD, with the mechanism thought to be low-level inﬂammation promoted by the release of cytokines (9). Perhaps these same cytokines inﬂuence tendon metabolism or response to injury and have a part to play in explaining the ﬁndings described in this review. This review may accentuate the association between adiposity and tendinopathy because investigators in the case– control studies often access pools of tendinopathy patients through specialist centers on secondary or tertiary referral. It can be speculated that these patients have not responded quickly to conservative treatment with their primary practitioner, which leads to referral. Therefore, in the case– control studies, we may be seeing an interaction of effects: adiposity as a risk factor for tendon injury, adiposity as a consequence of tendon injury, and also adiposity as a factor limiting recovery from tendon injury (14). This is supported by the sensitivity analysis that showed a clustering of positive ﬁndings among studies investigating clinical patient populations (81%) and also among studies using a case– control design (77%). It is highly likely that these observations are closely linked, because someone who seeks treatment for a condition (a patient) is almost automatically deﬁned as a case, and is therefore likely to be included in a case– control study. A clustering of positive results among the case– control studies is suggestive of selection bias (a well-recognized limitation of this design) inﬂuencing the ﬁndings. This ﬁnding highlights the need for well-controlled longitudinal studies examining the relationship between adiposity and tendinopathy. Finally, a limitation that should be kept in mind is the use of symptoms to diagnose tendon pathology. Pain of a Figure 3. Forest plot showing the relationship between adiposity and tendon injury. Odds ratios are shown on a logarithmic scale, with scores ⬎1 indicating increased adiposity among those with tendon injury. Dx ⫽ diagnosis; WC ⫽ waist circumference; WHR ⫽ waist to hip ratio; BMI ⫽ body mass index. 848 Gaida et al AUTHOR CONTRIBUTIONS Mr. Gaida had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Gaida, Bass, Cook. Acquisition of data. Gaida, Ashe, Cook. Analysis and interpretation of data. Gaida. Manuscript preparation. Gaida, Ashe, Bass, Cook. Statistical analysis. Gaida. 17. 18. 19. 20. REFERENCES 1. 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DOI 10.1002/art.24712 Submissions Invited for Themed Issue of Arthritis Care & Research: Drug Safety in the Rheumatic Diseases Arthritis Care & Research is soliciting manuscripts for a themed issue addressing drug safety in the treatment of rheumatic diseases, including but not limited to biologic agents. Manuscripts covering a broad range of topics related to the major theme are invited; for example, update on safety issues related to a speciﬁc drug or biologic agent, issues related to classes of treatments (e.g., anti–tumor necrosis factors [anti-TNFs]) and types of events (e.g., opportunistic infections in patients receiving anti-TNF agents), and issues related to different methodologies for assessing safety. Submissions may also describe more general issues related to treatment safety such as new or evolving methods of assessing or discussing safety, or beneﬁt or safety/ beneﬁt ratio with patients. Manuscripts from a wide range of disciplines relevant to safety are welcome. The issues will include regular submissions as well, but a certain number of pages will be reserved for manuscripts accepted in response to this solicitation. Manuscripts will be subject to the usual review process and all types of manuscripts (e.g., original articles, contributions from the ﬁeld, case studies, trainee rounds, reviews) are included in this solicitation. The deadline for submission is October 1, 2009. For further information, contact the editors of Arthritis Care & Research, Edward H. Yelin, PhD (Ed.Yelin@ucsf.edu) or Patricia P. Katz, PhD (Patti.Katz@ucsf.edu).