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Background: The research objectives of the 5-year and 10-year assessments in the Finnish degenerative meniscal lesion study (FIDELITY) are twofold: (1) to assess the long-term efficacy of arthroscopic partial meniscectomy (APM) in adults (age 35 to 65 years) with a degenerative meniscus tear and (2) to determine the respective effects of APM and degenerative meniscus tear on the development of radiographic and clinical knee osteoarthritis (OA).Methods and Design: FIDELITY is an ongoing multi-center, randomized, participant and outcome assessor blinded, placebo-surgery-controlled trial in 146 patients. This statistical analysis plan (SAP) article describes the overall principles for analysis of long-term outcomes (5-year and 10-year follow up), including how participants will be included in each analysis, the primary and secondary outcomes and their respective analyses, adjustments for covariates, and the presentation of the results. In addition, we will present the planned sensitivity and subgroup analyses.Discussion: To assess the long-term efficacy of APM on knee symptoms and function we are carrying out a long-term (5-year and 10-year) follow up of our placebo-surgery-controlled FIDELITY trial according to statistical principles outlined in detail in this document. As our second primary objective, whether APM (resection of torn meniscus tear) accelerates or delays the development of knee osteoarthritis in patients with an arthroscopically verified degenerative tear of the medial meniscus, a pre-registered follow-up is also carried out.Trial Registration: ClinicalTrials.gov, NCT00549172 (Arthroscopy in the Treatment of Degenerative Medial Meniscus Tear). Registered on 25 October 2007 (NCT00549172). ClinicalTrials.gov, NCT01052233 (Development of Knee Osteoarthritis After Arthroscopic Partial Resection of Degenerative Meniscus Tear). Registered on 20 January 2010. [ABSTRACT FROM AUTHOR]

Background: A distal forearm fracture is a very common injury causing both suffering and substantial health care costs. The incidence of this fracture type seemed to increase worldwide until the middle 1980's, but thereafter most reports have shown stable or decreasing rates. As few large studies have been presented lately we aimed to describe recent epidemiology and time trends of distal forearm fractures in adults. We paid special attention to fractures in working ages as they present challenges in terms of treatment and costs for sick-leave, and have not previously been thoroughly investigated.Methods: By use of population data from Statistics Sweden and official in- and out-patient register data of men and women (≥17 years) in Sweden (Skåne region), we ascertained distal forearm fractures and estimated age- and sex-specific rates and time-trends from year 1999 to 2010 (11.2 million person-years (py)).Results: The total incidence rate was 278 per 100,000 py (31,233 fractures) with 23% higher annual numbers 2010 compared with 1999. An increase in the annual age standardized incidence was found in men, +0.7% per annum (95% confidence interval (CI) 0.1, 1.4), and women, +0.9% (95% CI 0.5, 1.3), driven mainly by an increasing incidence in working ages (17-64 years). Also, expected demographic changes including a 25% population increase may result in 38% more fractures until 2050, compared to 2017.Conclusions: The incidence of distal forearm fractures in adults in southern Sweden is increasing, mainly driven by an increase in working ages. In combination with expected demographic changes these findings may present substantial challenges for the future. [ABSTRACT FROM AUTHOR]

Background: Due to low mortality rate of musculoskeletal disorders (MSK) less attention has been paid to MSK as underlying cause of death in the general population. The aim was to examine trend in MSK as underlying cause of death in 58 countries across globe during 1986-2011.Methods: Data on mortality were collected from the WHO mortality database and population data were obtained from the United Nations. Annual sex-specific age-standardized mortality rates (ASMR) were calculated by means of direct standardization using the WHO world standard population. We applied joinpoint regression analysis for trend analysis. Between-country disparities were examined using between-country variance and Gini coefficient. The changes in number of MSK deaths between 1986 and 2011 were decomposed using two counterfactual scenarios.Results: The number of MSK deaths increased by 67% between 1986 and 2011 mainly due to population aging. The mean ASMR changed from 17.2 and 26.6 per million in 1986 to 18.1 and 25.1 in 2011 among men and women, respectively (median: 7.3% increase in men and 9.0% reduction in women). Declines in ASMR of 25% or more were observed for men (women) in 13 (19) countries, while corresponding increases were seen for men (women) in 25 (14) countries. In both sexes, ASMR declined during 1986-1997, then increased during 1997-2001 and again declined over 2001-2011. Despite decline over time, there were substantial between-country disparities in MSK mortality and its temporal trend.Conclusions: We found substantial variations in MSK mortality and its trends between countries, regions and also between sex and age groups. Promoted awareness and better management of MSK might partly explain reduction in MSK mortality, but variations across countries warrant further investigations. [ABSTRACT FROM AUTHOR]

Background: The use of mapping algorithms have been suggested as a solution to predict health utilities when no preference-based measure is included in the study. However, validity and predictive performance of these algorithms are highly variable and hence assessing the accuracy and validity of algorithms before use them in a new setting is of importance. The aim of the current study was to assess the predictive accuracy of three mapping algorithms to estimate the EQ-5D-3L from the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) among Swedish people with knee disorders. Two of these algorithms developed using ordinary least squares (OLS) models and one developed using mixture model. Methods: The data from 1078 subjects mean (SD) age 69.4 (7.2) years with frequent knee pain and/or knee osteoarthritis from the Malmö Osteoarthritis study in Sweden were used. The algorithms' performance was assessed using mean error, mean absolute error, and root mean squared error. Two types of prediction were estimated for mixture model: weighted average (WA), and conditional on estimated component (CEC). Results: The overall mean was overpredicted by an OLS model and underpredicted by two other algorithms (P< 0.001). All predictions but the CEC predictions of mixture model had a narrower range than the observed scores (22 to 90%). All algorithms suffered from overprediction for severe health states and underprediction for mild health states with lesser extent for mixture model. While the mixture model outperformed OLS models at the extremes of the EQ-5D-3D distribution, it underperformed around the center of the distribution. Conclusions: While algorithm based on mixture model reflected the distribution of EQ-5D-3L data more accurately compared with OLS models, all algorithms suffered from systematic bias. This calls for caution in applying these mapping algorithms in a new setting particularly in samples with milder knee problems than original sample. Assessing the impact of the choice of these algorithms on cost-effectiveness studies through sensitivity analysis is recommended. [ABSTRACT FROM AUTHOR]

Background: While the impact of knee pain and knee osteoarthritis (OA) on health-related quality of life (HRQoL) has been investigated in the literature, there is a lack of knowledge on the impact of different definitions of OA on HRQoL. The main aim of this study was to measure and compare the impact of knee OA and its different definitions on HRQoL in the general population.Methods: A random sample of 1300 participants from Malmö, Sweden with pain in one or both knees in the past 12 months with duration ≥4 weeks and 650 participants without were invited to clinical and radiographic knee examination. A total of 1527 individuals with a mean (SD) age 69.4 (7.2) participated and responded to both generic (EQ-5D-3L) and disease-specific (the Knee injury and Osteoarthritis Outcome Score) questionnaires. Knee pain was defined as pain during the last month during most of the days. Knee OA was defined radiographically (equivalent to Kellgren and Lawrence grade ≥2) and clinically according to the American College of Rheumatology (ACR) criteria.Results: Of participants with either knee pain or knee OA or both, 7 % reported no problem for the EQ-5D-3L attributes. The corresponding proportion among references (neither knee pain nor OA) was 42 %. The participants with knee pain and OA had all HRQoL measures lower compared to those with knee pain but no OA. The ACR clinical definition of knee OA was associated with lower HRQoL than the definition based on radiographic knee OA (adjusted difference -0.08 in UK EQ-5D-3L index score).Conclusions: Applying different definitions of knee OA result in different levels of HRQoL and this is mainly explained by the knee pain experience. These differences may lead to discrepant conclusions from cost-utility analyses. [ABSTRACT FROM AUTHOR]

Background: The aim was to assess time trend of mortality with musculoskeletal disorders (MSD) as underlying cause of death in Sweden from 1997 to 2013.Methods: We obtained data on MSD as underlying cause of death across age and sex groups from the National Board of Health and Welfare's Cause of Death Register. Age-standardized mortality rates per million population for all MSD, its six major subgroups, and all other ICD-10 (International Classification of Disease) chapters were calculated. We computed the average annual percent change (AAPC) in the mortality rates across age/sex groups using joinpoint regression analysis by fitting a regression line to the natural logarithm of the age-standardized mortality rates and calendar year as a predictor.Results: There were a total of 7 976 deaths (0.5% of all causes deaths) with MSD as the underlying cause of death (32.5% of these deaths caused by rheumatoid arthritis [RA]). The overall age-standardized mortality rates (95% CI) were 16.0 (15.4 to 16.7) and 24.9 (24.1 to 25.7) per million among men and women, respectively (women/men rate ratio 1.55; 95%CI 1.47 to 1.63). On average, mortality rate declined by 2.3% per year and only circulatory system mortality had a more favourable decline than mortality with MSD as underlying cause. Among MSD the highest decline was observed in RA (3.7% per year) during study period. Across age groups, while there were generally stable or declining trends, spondylopathies and osteoporosis mortality among people ≥ 75 years increased by 2 and 1.5% per year, respectively.Conclusion: In overall, mortality with MSD as underlying cause has declined in Sweden over last two decades, with the highest decline for RA. However, there are variations across MSD subgroups which warrants further investigations. [ABSTRACT FROM AUTHOR]

Background Comparative data on sick leave within musculoskeletal disorders (MSDs) is limited. Our objective was to give a descriptive overview of sick leave patterns in different MSDs. Methods Using electronic medical records, we collected information on dates and diagnostic codes for all available sick leave certificates, during 2 years (2009-2010), in the North Western part of the Skåne region in Sweden (22 public primary health care centres and two general hospitals). Using the International Classification of Diseases (ICD) 10 codes on the certificates we studied duration, age and sex distribution and recurrent periods of sick leave for six strategically chosen MSDs; low back pain (M54) disc disorders (M51), knee osteoarthritis (M17) hip osteoarthritis (M16) rheumatoid arthritis (M05-M06) and myalgia (M79). Results All together 20 251 sick leave periods were issued for 16 673 individuals 16-64 years of age (53% women). Out of the selected disorders, low back pain and myalgia had the shortest sick leave periods, with a mean of 26 and 27 days, respectively, while disc disorders and rheumatoid arthritis had the longest periods with a mean of 150 and 147 days. For low back pain and myalgia 27% and 26% of all sick leave was short (8-14 days) and only 11% and 13%, were long (=90 days). For the other selected MSDs, less than 5% of the periods were short. For disc disorders, hip osteoarthritis and rheumatoid arthritis, more than 60% of the periods were long (p > 0.001). For back disorders and myalgia most periods were issued in the age groups between 40-49, with similar patterns for women and men. Osteoarthritis and rheumatoid arthritis had most periods in the age groups of 50-64, and patterns for women and men differed. Low back pain, rheumatoid arthritis and myalgia had the greatest share of recurrent sick leave (31%, 34% and 32% respectively). Conclusion Duration, age and sex distribution and numbers of recurrent sick leave varies considerably between different MSDs. This underscores the importance of using specified diagnosis, in sick leave research as well as in planning of treatment and rehabilitation and evaluation of prognosis. [ABSTRACT FROM AUTHOR]

Background: Ischemic heart disease and stroke are two severe types of cardiovascular disease (CVD), a major contributor to the global burden of disease. The preventive framework currently includes promotion of both adequate cardiorespiratory and muscular fitness. Although muscle fitness is established as an indicator of health, it is currently unknown whether muscle strength is associated with later CVD independently of cardiorespiratory fitness. Methods: We studied 38,588 Swedish men who in 1969 to 1970 (typically aged 18 years) completed compulsory conscription. Using the mean standardized score of three isometric muscle strength tests performed at conscription (hand grip, elbow flexion and knee extension), we categorized the subjects into three groups with the 25th to 75th percentile defining the reference category. We followed the cohort until 2012 for diagnosed CVD events and mortality via national health care registers and the national cause of death register. To estimate hazard ratios (HR) for CVD events (coronary heart disease or stroke) and CVD mortality we used Cox proportional hazard models adjusted for body mass index, smoking, alcohol consumption, cardiorespiratory fitness and socioeconomic status. Results: Men with high muscle strength in adolescence had a decreased risk of later CVD events (HR 0.88, 95% confidence interval 0.77 to 0.99), whereas we observed no increased risk in men with low muscle strength (0.99, 0.86 to 1.13). However, low muscle strength was associated with increased risk of CVD mortality during middle age (1.31, 1.02 to 1.67). Conclusions: Muscle strength in adolescent men is inversely associated with later CVD events and CVD mortality in middle age, independently of cardiorespiratory fitness and other important confounders. Thus, the role of muscle fitness in the prevention and pathogenesis of CVD warrants increased attention. [ABSTRACT FROM AUTHOR]

Background A high degree of meniscal body extrusion on knee magnetic resonance imaging has been shown to be strongly associated with development of knee osteoarthritis However, very little is known about meniscal position in the asymptomatic knee and its natural history. Hence our objective was to study meniscal body position and its change over 4 years in asymptomatic adults. Methods Cohort study using data from the Osteoarthritis Initiative (OAI) involving four clinical sites in United States (Baltimore, Maryland, Pawtucket, Rhode Island, Columbus, Ohio, and Pittsburgh, Pennsylvania). We studied both knees from 118 subjects (mean age 55 years, 61% women, mean body mass index 24.4) from the OAI “non-exposed” reference cohort free of knee pain, radiographic knee osteoarthritis and risk factors for knee osteoarthritis at baseline. We assessed mid-coronal intermediate-weighted 3-Tesla magnetic resonance images from baseline and the 2- and 4-year follow-up visit. One observer measured tibia plateau, meniscal body width and meniscal body extrusion in both compartments. We calculated meniscal overlap distance on the tibial plateau,% coverage, and extrusion index compared to tibia width. Potential trends in position over the 4-year period were evaluated using a linear mixed-effects regression model. Results The mean (SD) values at baseline for medial meniscal body extrusion and overlap distance were 1.64 mm (0.92) and 10.1 mm (3.5), and coverage was 34.4% (11.9). The corresponding values for the lateral compartment were 0.63 mm (0.73), 9.8 mm (2.4), and 31.0% (7.7). Medial meniscus body extrusion index was greater in female knees (p = 0.03). There was slight increase in medial meniscal body extrusion over 4 years (0.040 mm/year [95% CI: 0.019-0.062]). The other variables were relatively stable. Conclusion In asymptomatic adults, the relative degree of meniscus body extrusion is more pronounced in female knees. Although a slight increase in extrusion over time was noted for the medial body, positions were relatively stable within subjects over time. [ABSTRACT FROM AUTHOR]

Background: To assess the annual consultation prevalence and new onset consultation rate for doctor-diagnosed shoulder pain conditions. Methods: We identified all residents in the southernmost county in Sweden who received a shoulder pain diagnosis during 2006 (ICD-10 code M75). In subjects who did not consult due to such disorders during 2004 and 2005, we estimated the new onset consultation rate. The distribution of specific shoulder conditions and the length of the period of repeated consultation were calculated. Results: Annual consultation prevalence was 103/10 000 women and 98/10 000 men. New onset consultation rate was 80/10 000 women (peak in age 50-59 at 129/10 000) and 74/10 000 men (peak in age 60-69 at 116/10 000). About one fifth of both genders continued to consult more than three months after initial presentation, but only a few percent beyond two years. Rotator cuff - and impingement syndromes were the most frequent diagnoses. Conclusion: The annual consultation prevalence for shoulder pain conditions (1%) was similar in women and men, and about two thirds of patients consulted a doctor only once. Impingement and rotator cuff syndromes were the most frequent diagnoses. [ABSTRACT FROM AUTHOR]

Background: There have been reports both supporting and refuting an inverse relationship between hip fracture and hip osteoarthritis (OA). We explore this relationship using a case-control study design. Methods: Exclusion criteria were previous hip fracture (same side or contralateral side), age younger than 60 years, foreign nationality, pathological fracture, rheumatoid arthritis and cases were radiographic examinations were not found in the archives. We studied all subjects with hip fracture that remained after the exclusion process that were treated at Akureyri University Hospital, Iceland 1990-2008, n = 562 (74% women). Hip fracture cases were compared with a cohort of subjects with colon radiographs, n = 803 (54% women) to determine expected population prevalence of hip OA. Presence of radiographic hip OA was defined as a minimum joint space of 2.5 mm or less on an anteroposterior radiograph, or Kellgren and Lawrence grade 2 or higher. Possible causes of secondary osteoporosis were identified by review of medical records. Results: The age-adjusted odds ratio (OR) for subjects with hip fracture having radiographic hip OA was 0.30 (95% confidence interval [95% CI] 0.12-0.74) for men and 0.33 (95% CI 0.19-0.58) for women, compared to controls. The probability for subjects with hip fracture and hip OA having a secondary cause of osteoporosis was three times higher than for subjects with hip fracture without hip OA. Conclusion: The results of our study support an inverse relationship between hip fractures and hip OA. [ABSTRACT FROM AUTHOR]

Background: Large variations in pain and function are seen over time in subjects at risk for and with radiographic knee osteoarthritis (OA). We hypothesized that this variation may be related not only to knee OA but also to patient characteristics. The objective of this study was to investigate the influence of age, gender, and body mass index (BMI) on clinically relevant change in pain and function over two years in subjects at high risk for or with knee OA. Methods: We assessed 143 individuals (16% women, mean age 50 years [range 27-83]) twice; 14 and 16 years after isolated meniscectomy. Subjects completed one disease-specific questionnaire, the Knee injury and Osteoarthritis Outcome Score (KOOS) and one generic measure, the SF-36. Individuals with a BMI between 25 and 29.9 were considered overweight, while individuals with a BMI of 30 or more were considered obese. Results: Subjects aged 46-56 (the middle tertile) were more likely to change (=10 points on a 0- 100 scale) in the KOOS subscale Activities of Daily Living (ADL) than younger subjects (odds ratio [OR] 4.5, 95% confidence interval [95% CI] 1.5-13.0). Essentially the same result was obtained after adjusting for baseline values. Overweight or obesity was a risk factor for clinically relevant change for knee pain (OR 2.4, 95% CI 1.0 - 5.8, OR 4.0, 95% CI 1.2 - 13.6) and obesity for change in ADL (OR 4.3, 95% CI 1.2 - 15.4). The results did not remain significant when adjusted for the respective baseline value. Being symptomatic was strongly associated with increased variation in pain and function while presence or absence of radiographic changes did not influence change over two years in this cohort. Conclusion: In a population highly enriched in early-stage and established knee OA, symptomatic, middle-aged, and overweight or obese subjects were more likely to vary in their knee function and pain over two years. The natural course of knee pain and function may be associated with subject characteristics such as age and BMI. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have, so far, identified factors associated with increased risk for incident or progressive OA, such as age, sex, heredity, obesity, and joint injury. There is, however, a paucity of long-term data that provide information on the nature of disease progression on either group or individual levels. Such information is needed for identification of study cohorts and planning of clinical trials. The aim of the study was, thus, to assess the variation in pain and function on group and individual level over 2 years in previously meniscectomized individuals with and without radiographic knee osteoarthritis (OA). Methods: 143 individuals (16% women, mean age at first assessment 50 years [range 27.83]) were assessed twice; approximately 14 and 16 years after isolated meniscectomy, with a median interval of 2.3 years (range 2.3-3.0). Radiographic OA (as assessed at the time of second evaluation) was present in the operated knee in 40%, and an additional 19% had a single osteophyte grade 1 in one or both of the tibiofemoral compartments. Subjects completed the self-administered and disease-specific Knee injury and Osteoarthritis Outcome Score (KOOS). Results: There were no significant changes in the group mean KOOS subscale scores over the 2-year period. However, a great variability over time was seen within individual subjects. Out of 143 subjects, 16% improved and 12% deteriorated in the subscale Pain, and 13% improved and 14% deteriorated in the subscale ADL ≥ 10 points (the suggested threshold for minimal perceptible clinical change). Similar results were seen for remaining subscales. Conclusion: Group mean scores for this study cohort enriched in incipient and early-stage knee OA were similar over 2 years, but pain, function and quality of life changed considerably in individuals. These results may be valid also for other at risk groups with knee OA, and motivate further careful examination of the natural history of OA, as well as properties of the OA outcome instruments used. Longitudinal outcome data in OA studies need to be analyzed both on an individual and a group level. [ABSTRACT FROM AUTHOR]

Background: Meniscus extrusion or hypertrophy may occur in knee osteoarthritis (OA). However, currently no data are available on the position and size of the meniscus in asymptomatic men and women with normal meniscus integrity., Methods: Three-dimensional coronal DESSwe MRIs were used to segment and quantitatively measure the size and position of the medial and lateral menisci, and their correlation with sex, height, weight, and tibial plateau area. 102 knees (40 male and 62 female) were drawn from the Osteoarthritis Initiative "non-exposed" reference cohort, including subjects without symptoms, radiographic signs, or risk factors for knee OA. Knees with MRI signs of meniscus lesions were excluded., Results: The tibial plateau area was significantly larger (p < 0.001) in male knees than in female ones (+23% medially; +28% laterally), as was total meniscus surface area (p < 0.001, +20% medially; +26% laterally). Ipsi-compartimental tibial plateau area was more strongly correlated with total meniscus surface area in men (r = .72 medially; r = .62 laterally) and women (r = .67; r = .75) than contra-compartimental or total tibial plateau area, body height or weight. The ratio of meniscus versus tibial plateau area was similar between men and women (p = 0.22 medially; p = 0.72 laterally). Tibial coverage by the meniscus was similar between men and women (50% medially; 58% laterally), but "physiological" medial meniscal extrusion was greater in women (1.83 ± 1.06mm) than in men (1.24mm ± 1.18mm; p = 0.011)., Conclusions: These data suggest that meniscus surface area strongly scales with (ipsilateral) tibial plateau area across both sexes, and that tibial coverage by the meniscus is similar between men and women.

Introduction: Aggrecanase cleavage at the (392)Glu-(393)Ala bond in the interglobular domain (IGD) of aggrecan, releasing N-terminal (393)ARGS fragments, is an early key event in arthritis and joint injuries. We determined whether synovial fluid (SF) levels of ARGS-aggrecan distinguish subjects with progressive radiographic knee osteoarthritis (ROA) from those with stable or no ROA., Methods: We studied 141 subjects who, at examination A, had been given meniscectomies an average of 18 years earlier (range, 15 to 22 years). Seventeen individuals without surgery, and without known injury to the menisci or cruciate ligaments, were used as references. At examinations A and B, with a mean follow-up time of 7.5 years, we obtained SF and standing tibiofemoral and skyline patellofemoral radiographs. SF ARGS-aggrecan was measured with an electrochemiluminescence immunoassay, and we graded radiographs according to the OARSI atlas. The association between SF ARGS levels at examination A and progression of radiographic features of knee OA between examinations A and B was assessed by using logistic regression adjusted for age, gender, body mass index, and time between examinations, and stratified by ROA status at examination A., Results: We found a weak negative association between SF ARGS concentrations and loss of joint space: the likelihood of progression of radiographic joint space narrowing decreased 0.9 times per picomole per milliliter increase in ARGS (odds ratio (OR) 0.89; 95% confidence interval (CI), 0.79 to 0.996). In subjects with and without preexisting ROA at examination A, the association was OR, 0.96; 0.81 to 1.13; and 0.77; 0.62 to 0.95, respectively. Average levels of SF ARGS 18 years after meniscectomy were no different from those of reference subjects and were not correlated to radiographic status at examination A., Conclusions: In subjects with previous knee meniscectomy but without ROA, levels of SF ARGS-aggrecan were weakly and inversely associated with increased loss of joint space over a period of 7.5 years.

Introduction: The objective of this study was to examine the association between occupation and osteoarthritis (OA) leading to total knee (TKR) or hip (THR) joint replacement., Methods: The following is the case-control study design. All patients still living in Iceland who had had a TKR or THR due to OA as of the end of 2002 were invited to participate. First degree relatives of participating patients served as controls. N=1,408 cases (832 women) and n=1,082 controls (592 women), 60 years or older and who had adequately answered a questionnaire were analyzed. Occupations were classified according to international standards. Inheritance of occupations was calculated by using the Icelandic Genealogy Database., Results: The age adjusted odds ratio (OR) for male farmers getting a TKR due to OA was 5.1 (95% confidence interval (CI) 2.1 to 12.4) and for a male farmer getting a THR due to OA the OR was 3.6 (95% CI 2.1 to 6.2). The OR for a fisherman getting a TKR was 3.3 (95% CI 1.3 to 8.4). No other occupations showed increased risk for men. For women there was no increased risk for any occupation. Farming and fishing were also the occupations that showed the greatest degree of inheritance., Conclusions: These results support an association in males between occupations with heavy physical load and both TKR and THR for OA.