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      Use of statins is associated with a lower prevalence of generalised osteoarthritis

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          Abstract

          Recent reports, from The Netherlands1 and the UK,2 suggest that statins have a modifying role in osteoarthritis (OA) using different outcome definitions, specifically radiographic OA in the Rotterdam cohort and general practitioner diagnosis from a national database in the UK study. On the other hand, a large longitudinal study from the USA found that statin use was not associated with improvements in knee pain, function or structural progression over a 4-year period.3 A separate US longitudinal study in elderly women found that statin use may be associated with an increased risk of developing incident radiographic hip OA.4 The discrepancies between published studies on statins and OA may be due to methodological factors as has been discussed elsewhere.5 Studies of generalised OA suggest the potential role of systemic processes in disease pathogenesis.6 It has been hypothesised, based on evidence from in vitro studies, that a dysfunction in lipid metabolism may play a role in the pathogenesis of OA.7 It is therefore possible that lipid dysregulation may be involved more in generalised polyarticular OA than in single large joint OA. Generalised OA (GOA) refers to the involvement of at least three joints, or a group of joints, for example, the interphalangeal (IP) joints. The nodal type of GOA, characterised by Heberden's and Bouchard's nodes predominates in women and associates with underlying radiographic IP OA.8 There is no agreed consensus definition for generalised OA, but the presence of IP nodes has been shown to result in a different profile of risk factors for both hip and knee OA.9 In order to test if statin use is associated with generalised nodal OA, we used data from the Genetics of OA and Lifestyle (GOAL) study, a large case-control study involving clinically severe OA cases, with full radiographic assessment, recruited from secondary care. 8 We focused on the following eight outcomes: (1) nodal OA defined as Heberden's or Bouchard's nodes affecting two or more rays of both hands; (2) knee OA defined as a Kellgren–Lawrence (K/L) score ≥2 at the tibiofemoral compartment of either knee excluding hip OA; (3) radiographic hip OA defined as a K/L ≥2 at either hip excluding knee OA; (4) hip and knee OA pelvis K/L ≥2 at either hip and tibiofemoral ≥2 at either knee; (5) generalised knee OA defined as knee OA in addition to nodal status excluding hip OA; (6) generalised hip OA defined as hip OA in addition to nodal status excluding knee OA; (7) generalised hip and knee OA; (8) any GOA (the sum of 5, 6 and 7 above). Details on X-rays and patient recruitment have been reported elsewhere.9 The descriptive characteristics of study participants are shown in table 1. Table 1 Descriptive characteristics of study participants Statin use* Characteristic No Yes n 2510 661 Years on statin medication 0 4.28 (3.39) Age years mean (SD) 65.96 (8.10) 68.8 (6.52) BMI kg/m2 mean (SD) 29.10 (5.27) 29.92 (5.19) Years with joint pain mean (SD)† 8.49 (9.46) 8.55 (9.88) F (n=1537) % (n) 51.3% (n=1288) 37.7% (n=249) Cardiovascular disease (n=1679) % (n)‡ 43.1% (n=1082) 90.3% (n=597) Medication for pain (n=1767) % (n) 54.9% (n=1378) 58.8% (n=389) Ever-smoked: ex-smokers (n=1487) and current smokers (n=429) % (n) 58.0% (n=1457) 69.4% (n=459) Controls (n=805) % (n) 26.7% (n=669) 20.6% (n=136) Nodal OA (n=106) % (n)§ 3.3% (n=83) 3.5% (n=23) Knee OA (n=729) % (n)¶ 21.8% (n=546) 27.7% (n=183) Hip OA (n=499) % (n)¶ 15.9% (n=399) 15.1% (n=100) Hip and knee OA (n=427) % (n)¶ 12.7% (n=318) 16.5% (n=109) Generalised knee OA: nodal+knee (n=238) 7.5% (n=188) 7.6% (n=50) Generalised hip OA: nodal+hip (n=142) 4.7% (n=118) 3.6% (n=24) Generalised hip and knee OA: nodal+hip and knee (n=225) 7.5% (n=189) 5.4% (n=36) *Study participants underwent a home visit9 and the research nurse reviewed medications and repeat prescriptions from participants. Participants were classified as being on statin medication if they were taking any of the following medications: pravastatin, rosuvastatin, simvastatin, atorvastatin or fluvastatin. No information on dose was available. †For patients with only knee OA (nodal or not) this is the years with knee pain; for patients with hip OA, the years with hip pain; for patients with both knee and hip OA, this is the largest of years with hip or knee pain; controls are not included, for asymptomatic cases it is 0. ‡Comorbidities were evaluated by nurse-applied questionnaire. A participant is considered to have cardiovascular disease if they replied yes to the question ‘have you been diagnosed by your general practitioner or a specialist to have heart disease or hypertension’. §The presence of Heberden's and Bouchard's nodes was assessed by a nurse. The nodal phenotype was defined as Heberden's and/or Bouchard's nodes that affected at least two rays of each hand. ¶Hip OA was defined as Kellgren–Lawrence at the pelvis (K/L) ≥2) knee OA cases (K/L ≥2)=1617 controls. BMI, Body Mass Index; OA, osteoarthritis. After adjustment for confounders we find no evidence for an association between nodal OA, hip OA or knee OA and use of statins (table 2). However, use of statins is associated with a lower prevalence of the GOA phenotype. This association remains statistically significant after further adjustment for a diagnosis of various comorbidities (table 2). Table 2 Association between statin use and prevalence of OA phenotypes in the GOAL study   Adjusted for age, sex, BMI Adjusted for additional covariates OR* 95% CI p Value OR† 95% CI p Value Nodal OA 1.11 (0.59 to 2.09) 0.74 1.04 (0.53 to 2.05) 0.91 Hip OA 0.98 (0.70 to 1.38) 0.93 1.00 (0.68 to 1.48) 0.99 Knee OA 1.32 (0.99 to 1.75) 0.06 1.27 (0.91 to 1.77) 0.15 Knee and hip OA 1.04 (0.75 to 1.43) 0.83 0.92 (0.63 to 1.34) 0.66 Generalised hip OA 0.85 (0.52 to 1.38) 0.51 0.80 (0.47 to 1.35) 0.40 Generalised knee OA 0.91 (0.59 to 1.41) 0.67 0.79 (0.46 to 1.35) 0.40 Generalised knee and hip OA 0.66 (0.42 to 1.01) 0.06 0.63 (0.38 to 1.04) 0.07 All generalised OA 0.75 (0.59 to 0.94) 0.012 0.76‡ (0.59 to 0.97) 0.028 *OR=OR for association between statin use and OA. Association was assessed by logistic regression, with hip OA, knee OA or generalised OA being the outcome variables, statin use (yes/no) the independent variable, and including age, sex and Body Mass Index (BMI), as covariates. †Further adjustment for a diagnosis of hypertenstion or any form of cardiovascular comorbidity, smoking (never smoked=0, ex-smoker=1, current smoker=2) and use of pain medication was also performed. ‡Additional adjustment for stroke, kidney disease, type 2 diabetes, and years with pain at the target joint OR=0.77 (0.60 to 0.99) p<0.048. GOAL, genetics of OA and lifestyle; OA, osteoarthritis. Bold font indicates a statistically significant (p<0.05) result. The present study has a number of limitations: its cross-sectional nature, a hospital-based case control design, and the lack of statin dose information. Nonetheless, our data provide further evidence supporting that statin use may affect OA although in our case only a specific OA phenotype (ie, generalised nodal OA). Given the lack of structure-modifying drugs,10 it would be much welcome news if statins were proved to reduce OA risk or progression even if this was only on a subset of patients. Further studies primarily designed to address this question are warranted.

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          Is progressive osteoarthritis an atheromatous vascular disease?

          Growing evidence from epidemiological studies suggests that osteoarthritis (OA) is linked to atheromatous vascular disease. This hypothesis article proposes that OA, or at least OA structural progression, may be an atheromatous vascular disease of subchondral bone. Further epidemiological studies, imaging investigations of relevant blood vessels, and trials of the effects of statins on the prevention and treatment of OA are needed to examine this hypothesis.
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            Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study.

            Osteoarthritis is the most frequent chronic joint disease causing pain and disability. Besides biomechanical mechanisms, the pathogenesis of osteoarthritis may involve inflammation, vascular alterations and dysregulation of lipid metabolism. As statins are able to modulate many of these processes, this study examines whether statin use is associated with a decreased incidence and/or progression of osteoarthritis. Participants in a prospective population-based cohort study aged 55 years and older (n=2921) were included. x-Rays of the knee/hip were obtained at baseline and after on average 6.5 years, and scored using the Kellgren and Lawrence score for osteoarthritis. Any increase in score was defined as overall progression (incidence and progression). Data on covariables were collected at baseline. Information on statin use during follow-up was obtained from computerised pharmacy databases. The overall progression of osteoarthritis was compared between users and non-users of statins. Using a multivariate logistic regression model with generalised estimating equation, OR and 95% CI were calculated after adjusting for confounding variables. Overall progression of knee and hip osteoarthritis occurred in 6.9% and 4.7% of cases, respectively. The adjusted OR for overall progression of knee osteoarthritis in statin users was 0.43 (95% CI 0.25 to 0.77, p=0.01). The use of statins was not associated with overall progression of hip osteoarthritis. Statin use is associated with more than a 50% reduction in overall progression of osteoarthritis of the knee, but not of the hip.
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              Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes.

              To quantify the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) based on the presence versus absence of multiple interphalangeal nodes in 2 or more rays of the fingers of each hand in patients with large joint osteoarthritis (OA). A group of 3,800 patients with large joint OA who underwent total joint replacement (1,201 of whom had the nodal phenotype) and 1,906 control subjects from 2 case-control studies and a population-based cohort in the UK were studied. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for the risk of total joint replacement in association with age, sex, body mass index (BMI), height, and prevalence of the T allele in the GDF5 rs143383 polymorphism. ORs for total joint replacement were compared between cases of nodal OA and cases of non-nodal OA and between patients who underwent TKR and those who underwent THR. Age, sex, and BMI had significantly higher ORs for an association with total joint replacement in nodal OA cases than in non-nodal OA cases. The GDF5 polymorphism was significantly associated with THR in cases of nodal OA, but not in cases of non-nodal OA, and increased height was a risk factor for THR in non-nodal OA cases only. Female sex was a protective risk factor for TKR in non-nodal OA cases (OR 0.60, 95% CI 0.52-0.70) but was predisposing for TKR in the nodal form of OA (OR 1.83, 95% CI 1.49-2.26). The nodal phenotype was associated with a significantly higher risk of undergoing both THR and TKR (OR 1.46, 95% CI 1.09-1.94) and also a significantly higher risk of bilateral TKR (OR 1.70, 95% CI 1.37-2.11), but, paradoxically, was associated with a lower risk of bilateral THR (OR 0.72, 95% CI 0.56-0.91). Nodal and non-nodal forms of large joint OA have significantly different risk factors and outcomes, indicating a different etiology for the 2 forms of OA. With regard to the likelihood of undergoing THR, this appears to be, at least in part, genetically determined.
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                Author and article information

                Journal
                Ann Rheum Dis
                Ann. Rheum. Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                May 2014
                17 December 2013
                : 73
                : 5
                : 943-945
                Affiliations
                [1 ]Academic Rheumatology, University of Nottingham, Clinical Sciences Bld, Nottingham City Hospital, Nottingham, UK
                [2 ]Institute of Population Health,University of Manchester, Oxford Road, Manchester, UK
                [3 ]Respiratory, Inflammation, Autoimmunity iMed, AstraZeneca AB, Mölndal, Sweden
                Author notes
                [Correspondence to ] Ana M Valdes, Academic Rheumatology, Clinical Sciences Building, Nottingham City Hospital Hucknall Road, Nottingham, NG5 1PB, UK; ana.valdes@ 123456nottingham.ac.uk
                Article
                annrheumdis-2013-204382
                10.1136/annrheumdis-2013-204382
                3995213
                24347568
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

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