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What are the best markers for disease progression in osteoarthritis (OA)?
Best Practice & Research Clinical Rheumatology 24 (2010) 81–92
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What are the best markers for disease progression in osteoarthritis (OA)? P.P. Cheung, MD, Articulum Research Fellow *, L. Gossec, MD, PhD, Rheumatologist 1, M. Dougados, MD, Professor of Rheumatology Paris Descartes University, Medicine Faculty, UPRES-EA 4058, APHP, Rheumatology B Department, Cochin Hospital, Paris, France
Keywords: osteoarthritis prognosis progression
To be able to prevent progression of osteoarthritis, the knowledge of prognostic factors of this progression is important. If certain prognostic factors are modifiable, they may enhance our ability to reduce osteoarthritis progression. Even if these prognostic factors are not modifiable, they can still be used to identify high-risk groups, which may have implications for patient information and the perspective of medical treatment. Prognostic factors of progression are reviewed here, mainly for hip and knee osteoarthritis as most data available concern these localisations. Areas of further research are highlighted. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Radiographic osteoarthritis (OA) is frequent and potentially debilitating. Due to an ageing population, the prevalence of OA is expected to increase in the next decades [1]. In western countries, the increase in prevalence in the next 20 years is expected to be about 40%, making OA the fourth leading cause of disability [1]. Little is known, however, about the course of disability over time in patients with OA. To optimise the management of OA, it is important to increase our knowledge regarding the predictors of progression of OA. If certain prognostic factors are modifiable, they may enhance our ability to reduce OA progression. Even if they are not modifiable, it can still be used to identify high-risk groups, which
* Corresponding author. Tel.: þ33 1 58412606; Fax: þ33 1 43257884. E-mail addresses: [email protected] (P.P. Cheung), [email protected] (L. Gossec), maxime.dougados@cch. aphp.fr (M. Dougados). 1 Tel.: þ33 1 58412606; Fax: þ33 1 43257884. 1521-6942/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.08.009
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may have implications for patient information and medical treatment [2]. Knowledge about modifiable factors and high-risk groups is also relevant for clinical research, such as studies evaluating therapeutic interventions, including disease-modifying therapies. Objective The objective of this review is to summarise available data pertaining to prediction of OA progression. Some necessary precisions Localisation of OA Although OA is frequent at several locations, that is, the lower limb joints (hip and knee), the spine and the fingers (hand OA), most data regarding prognostic factors of progression are available for hip and knee OA, for which this review concentrates mostly on. How to define progression: symptoms versus X-rays Progression of OA can be assessed through symptoms (i.e., pain and/or functional consequences) [3]. Knowledge of functional consequences is essential for the development of optimal rehabilitation programmes in OA patients. Progression can also be defined through structural progression (generally assessed by radiologic progression on plain radiographs) [4–6]. Scoring techniques used include the Kellgren and Lawrence grading [7], measurement of joint space width (JSW) in millimetres or use of the Osteoarthritis Research Society International (OARSI) atlas [8]. Due to the contradictory association between radiologic OA and functioning [9–11], information about functional course cannot be derived from studies on radiologic progression. Another possible definition of progression is the requirement for total joint replacement, a surrogate marker of more severe spectrum of disease [12]. In this review, we present the available data which relate mostly to predictors of radiographic progression. Differences between data issued from trials and cohorts One of the difficulties is that data available regarding prognostic factors of progression of OA are issued from two main different sources: clinical trials (e.g., the Evaluation of the Chondromodulating Effect of Diacerein in Osteoarthritis of the Hip trial, ECHODIAH [13], a French multicentre randomised controlled trial in hip OA) and epidemiologic cohorts, population based or not (e.g., Hawker et al. [14], a large prospective population cohort study of 2128 individuals studying factors on progression of hip and knee OA with a median follow-up of 6.1 years). As patients participating in clinical trials do not reflect the general population [15], epidemiologic cohort data may be more relevant for clinical practice. However, both types of data are reported here, since many elements have been reported mainly in trials. For the purposes of this review, the current knowledge regarding prognostic factors of progression in OA will be divided into patient and disease characteristics. Part I. Patient characteristics predictive of OA progression The various patient characteristics studied in OA progression and the level of evidence are summarised in Table 1. Age There is moderate evidence that age is a risk factor for hip and knee OA progression Age is a risk factor for occurrence of OA but may not be a risk factor for progression of OA [16,17]. In a 12-year follow-up study of a general population of 239 patients, Schouten et al. [18] found
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Table 1 Patient characteristics and the strength of association in prediction of OA progression. Risk factor
Strength of association
Age Gender Malalignment of the knee Adduction moment of the knee Quadriceps strength Sports and running Nutrition Superolateral migration in hip OA Atrophic bone response in hip Injury and knee OA Meniscectomy and meniscal damage Chondrocalcinosis Obesity Smoking, anxiety and depression Genetics Hormones Insulin Growth Factor 1 Hyaluronic acid Bone mineral density
Moderate Conflicting Strong Limited Limited No evidence Limited to moderate Moderate Strong No relationship No evidence No evidence Conflicting No relationship Inconclusive Inconclusive Conflicting Moderate Conflicting
Strong ¼ majority of available studies showing positive association, Moderate ¼ fewer studies but positive association is shown is majority of these studies, Limited ¼ positive association is shown but there are limited studies, Conflicting ¼ there are positive and negative studies, Inconclusive ¼ there are studies but can neither conclude a positive or a negative association, No relationship ¼ majority of studies show no relationship.
a significant association between age and progression of knee OA, measured by the change in joint space width (JSW). This was only for the comparison of the fourth quartile (higher age) versus the first quartile (lower age) with an odds ratio, OR, of 3.84 (95% confidence interval, CI: 1.10–13.4) in patients over 60 years old. On the other hand, a number of studies found no significant association [19–22]. In hip OA, there appears to be conflicting evidence that age is a risk factor for hip OA progression, although several studies have shown this association [6,23]. Positive studies [13,24,25] such as ECHODIAH [13] analysed 507 patients with symptomatic hip OA. In patients over 65 years old at baseline, there was an OR of 1.9 (95% CI: 1.18–3.08) of having radiological progression of the hip at 12 months. By contrast, Conrozier et al.[26], in a prospective follow-up study of 1 year, found no association between age and OA hip progression measured radiographically (JSW). Hawker et al. [14] studied both hip and knee OA and showed that increased age had an increased hazard ratio (HR) ranging from 1.46 to 1.57 of undergoing total joint arthroplasty. Gender There is conflicting evidence that female sex is associated with progression of OA in the hip and there is no evidence for knee OA progression There is no evidence supporting that female sex is a risk factor for progression of knee OA [18,20–22,27–29]. There is conflicting evidence that female sex is associated with progression of OA in the hip with only one cohort study that reported a positive association. In the ECHODIAH trial [13], a greater proportion of women had more structural progression at 1 year and more women had undergone total hip arthroplasty at 5 years, with an HR of 1.4 (95% CI: 1.1–1.8) [30]. Malalignment of the knee There is strong evidence of varus and valgus malalignment for OA progression of knee Malalignment (either valgus or varus) concentrates loading on a focal area, to the level at which cartilage damage may occur, potentially leading to OA progression. The systematic review by Tanamas
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et al. [31] found that knee malalignment is a strong independent risk factor for progression of knee OA. This was supported in both high-quality radiographic [27,32–34] and magnetic resonance imaging (MRI) cohort studies [35–37]. Three studies [27,33,34] reported a statistically significant association between varus alignment and progression of OA measured by a decrease in JSW. In the study by Miyazaki et al. [27], varus alignment and progression of knee OA had an OR of 3.10, (95% CI: 1.07–9.12) in the univariate analysis, but not multivariate analysis. Cerejo et al. [33] and Miyazaki et al. [27] found a statistically significant relationship with progression of OA when there was valgus malalignment (ORs 10.44 and 4.89, respectively). The third study reported association of OA progression with varus and valgus malalignment (ORs 2.98 and 3.42, respectively) [34]. Adduction moment of the knee There is limited evidence that increase in adduction moment of the knee is a risk factor for progression of OA knee Biomechanical factors such as the adduction moment of the knee have been considered to be an influential factor producing medial joint force in joints with varus deformity with the magnitude correlating with OA disease severity [27,38,39]. The only study examining the risk of high adduction moment to OA progression in the knee investigated 106 patients with medial compartment OA followed up for 6 years [27]. With a 1% increase in adduction moment, the risk of progression was increased by 6.5 times. However, gait analysis systems are not readily available for this risk factor to be useful in clinical practice. Type of migration in hip OA There is moderate evidence of superolateral migration and progression of hip OA In two out of the three highest-quality cohort studies reported in a systematic review [6], a more rapid progression of hip OA was found in patients with a superolateral migration of the femoral head [13,26]. The third high-quality study reported a positive association with superior migration [29]. Atrophic bone response in hip There is strong evidence that atrophic bone response is a risk for hip OA progression From three cohort studies including two of high quality evaluating the association between atrophic bone response and progression of hip OA, all three reported a positive association [26,29,40]. Injury and knee OA There is no association of knee injury and progression of knee OA Cooper et al. [41] studied the relationship between previous knee injury and progression of OA, while Schouten et al. [18] studied the presence of knee injury including sporting injuries at follow-up. Both these studies reported no association. Meniscectomy/meniscal damage and knee OA There is evidence of the prognostic role of meniscal damage and meniscectomy for incident OA of the knee but not for progression of knee OA Studies of meniscal damage on progression of OA have mainly used patients who have undergone meniscectomy. There has been a clear increase in risk of incident OA in patients who have undergone meniscectomy [38]. On the other hand, the evidence for a relationship between meniscectomy and progression of OA is poor [18].
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Chondrocalcinosis There is no evidence for an association between chondrocalcinosis and progression of knee OA A number of cross-sectional studies have found an association between the presence and severity of OA with chondrocalcinosis; however, evidence for radiographic progression on X-rays is lacking. A study evaluating two prospective cohorts on the progression of knee OA using longitudinal MRI assessments of cartilage loss failed to show a positive association [42]. There is also a lack of association when measured by JSW [18]. However, some authors support an association between calcium pyrophosphate and OA progression [43,44]. Weight – body mass index (BMI) There is conflicting evidence that obesity measured by BMI is a risk factor for knee and hip OA progression Although obesity is a strong risk factor for incident (new-onset) tibiofemoral and hip OA [45], findings on the relationship between BMI and OA progression are inconsistent. The data from the Multicentre Osteoarthritis STudy (MOST), an epidemiologic study of knee OA, showed that obesity had no effect on progression in OA knees with varus alignment; however, it did increase the risk of progression in knees with neutral or valgus alignment [46]. In that study, Niu et al. explained that the stress on varus knees might be sufficient by itself to produce progression, and that excess load conferred by obesity may not be necessary as an additional factor. Knees with valgus alignment do not necessarily produce comparable valgus stress. The Rotterdam study, a large population cohort of 3585 patients, showed that a high body mass index (BMI) was associated with progression of knee OA (OR 3.2) but not with hip OA [25]. In the study by Cooper et al. [41], a significant relationship with BMI was only found in the comparison of the highest tertile versus the lowest tertile in the group with baseline K/L grade 2 or higher. Other studies found no statistically significant association [20,27,47]. The relationship between change in BMI and progression of OA was also investigated, but no statistically significant association was found [47]. Quadriceps strength There is no evidence that quadriceps strength is predictive of OA progression in the knee, except for perhaps the lateral compartment of the patellofemoral joint Quadriceps strengthening has been widely recommended for treatment of knee OA, but the impact of quadriceps strength on the course of OA progression is not well understood. Several authors found no difference in baseline quadriceps strength between those with and without OA progression [48,49]. Even when MRI was used as the outcome measure, there was no association between quadriceps strength and cartilage loss at the tibiofemoral joint [50]. In that particular study, quadriceps strength was protective against cartilage loss only at the lateral compartment of the patellofemoral joint with an OR of 0.4 (95% CI: 0.2–0.9) when comparing the highest versus the lowest tertile of strength. Greater quadriceps strength may prevent lateral offset and tilt of the patella, thus protecting against cartilage loss at the lateral compartment of the patellofemoral joint. Despite these findings, maintaining strong quadriceps is of benefit to those with knee OA but more work is needed to determine the type and frequency of exercise regimen that would be beneficial. Sports and running There is no evidence that sports and running increases risk of OA progression, more studies are needed Experimental studies in animals have indicated that running causes relatively little increased risk of OA progression, although it may stimulate osteophyte formation. The effect of sports activity on OA risk depends upon whether the activity was undertaken by a person with an already damaged joint or a normal joint. When protective mechanisms of damaged joints are impaired, it is vulnerable to the trans-articular loading that occurs with sports activity.
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There are limited clinical studies on risk factors in OA progression. There is no significant association between running and progression of OA in three studies [18,41,51]. Nutrition A significant relationship appears to be present between Vitamin D and C concentrations and OA progression, but more studies are needed to confirm this Nutrients may influence OA in at least four ways: protection from excessive oxidative damage, modulation of the inflammatory response, cellular differentiation and biological actions secondary to bone and collagen synthesis. McAlindon et al. [52,53] investigated the relationship between nutrition variables and progression of OA. For vitamin D, a low dietary intake and low serum level were associated with progression of knee OA (OR 4.05, 95% CI: 1.40–11.6 and OR 2.89, 95% CI: 1.01–8.25) for lowest versus highest tertile of dietary intake and serum levels, respectively. Furthermore, for vitamin C intake, a significant association was found (highest versus lowest tertile OR 0.26, 95% CI: 0.11–0.61). A significant association was reported for b-carotene intake only in the comparison of the highest versus the lowest tertile (middle versus lowest OR 1.42, 95% CI: 0.68–3.00). For vitamin E intake, no statistically significant association was found for the highest versus the lowest tertile. No relationship was found with vitamin B1, vitamin B6, niacin and folate. Smoking, anxiety and depression There is no evidence that smoking, anxiety or depression increases progression of OA Very little data have been found to indicate that smoking, anxiety or depression might increase progression of OA [18,22]. Genetics There is inconclusive evidence that genes contribute to OA progression The evidence for the role of genetics is unclear for OA progression, contrary to OA incidence [54]. Please refer to the article on genetics in the present issue for more information [55]. Hormones There is inconclusive evidence that oestrogen is protective of progression of knee OA Of particular interest has been the role of hormones such as oestrogen in the development of OA, largely from the observations of hormone replacement therapy (HRT) on the prevalence and incidence of OA. Oestrogen may have a beneficial effect on the structural progression of OA, particularly in the lower limbs. Lower circulating oestradiol and 2-hydroxyestrone levels have been associated with more prevalent and incident OA (defined radiographically) [56]. However, prospective cohort studies on oestrogen and effects on OA progression are lacking. Zhang et al. [57] investigated the relationship between oestrogen use and radiologic progression of knee OA in a prospective cohort study of 551 women showing current use of HRT had a moderate but non-statistically significant protective effect against progression of knee OA. No significant association was found between current use, and history of oestrogen use and progression of knee OA. Other biology There is conflicting evidence for insulin-like growth factor 1 (IGF-1) and moderate evidence for hyaluronic acid concentration regarding prediction of OA progression There are conflicting reports that insulin-like growth factor 1 (IGF-1) increases risk of OA progression [18,58]. Hyaluronic acid concentration may have a predictive value in knee osteoarthritis progression. This has been indicated in several studies [24,59–62]. Despite this, there are no studies supporting the hypothesis that intra-articular injection of hyaluronic acid would halt progression of OA.
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Bone mineral density There is conflicting evidence that high bone mineral density decreases progression in knee OA and therefore more studies are required Hart et al. [63] in their study on the incidence and progression of knee OA and relationship with bone density reported no statistically significant difference in bone density between the nonprogressive OA group and the progressive OA group. By contrast, Zhang et al. [64] found a minor association between high versus low bone density and progression of knee OA (fourth vs. first quartile OR 0.1, 95% CI: 0.03–0.3). Further studies are needed.
Part II. Disease characteristics The various disease characteristics studied in OA progression and level of evidence are summarised in Table 2.
Symptoms at baseline There is limited evidence that knee pain at baseline can predict OA progression in the knee Three studies found a significant relationship between knee pain at baseline and progression of knee OA [13,20,22].
Progression of symptoms over time There is limited evidence that persistence of symptoms predicts OA progression Dieppe et al.[65,66] reported a statistically significant relationship between the use of non-steroidal anti-inflammatory drugs and an overall measure of change of OA. In addition, Dougados et al. reported the level of pain and functional disability in conjunction with the amount of symptomatic treatment during a 1-year follow-up period explained 20% (p < 0.0001) of the variability in the JSW in the hip [13].
Initial radiographic severity There is conflicting evidence that initial severity of X-ray changes is predictive of OA progression in the knee Concerning severity of OA, only Wolfe and Lane [22] found a significant association between the initial JSW score and progression. Ledingham et al. [44] found a significant association with the change in attrition; in their study, no association was found between radiologic severity and change in the K/L score or JSW. Contradictory associations were found in the relationship between clinical severity and progression of knee OA [22,66].
Table 2 Disease characteristics and the strength of association in prediction of OA progression. Risk factor
Strength of association
Symptoms at baseline Progression of symptoms over time Initial radiographic severity Generalised OA Disease duration Serum COMP UCTX-II Inflammation/Synovitis Bone marrow lesions on MRI
Limited Limited Conflicting Strong Inconclusive Conflicting Conflicting Limited Limited
For explanations please refer to Table 1.
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Generalised OA There is strong evidence that presence of generalised OA is a risk factor for progression in OA of knee Several authors [18,44] reported a significant positive association between the presence of generalised OA (radiologically and/or clinically determined) and progression of knee OA. Disease duration There is inconclusive evidence for the association between length of disease duration and progression for OA Dieppe et al. [20] found no association with the duration of symptoms, and Wolfe and Lane [22] found a borderline significant association. Markers of bone or cartilage turnover There is conflicting evidence that serum cartilage oligomeric matrix protein (COMP) and urinary CTX-II are biomarkers predictive of OA progression There are many biomarkers under investigation potentially predictive of OA progression; however, progress has been slow. The only biomarker shown to be predictive of subsequent MRI-determined cartilage loss in knee OA has been the baseline level of serum COMP [66]. Conflicting reports of COMP are seen with progression determined by X-rays [60,61,68]. In terms of collagen-derived markers, Bettica et al. [69] found a relationship between urinary type I collagen telopeptide (uCTX-I) and progression of knee OA. uCTX-II has also been reported to be a good marker for progression of OA in the knee and hip [24,70,71]. However, uCTX-II has not predicted MRIdetermined cartilage loss [67]. Bruyere et al. [60] found no significant associations between osteocalcin, pyridinoline, or deoxypyridinoline and progression of knee OA. Inflammation There is limited evidence that inflammation (synovitis) is predictive of OA progression in the knee It is clear that synovitis can be present in patients with knee OA [72,73]. Ayral et al. performed a multicentre, longitudinal arthroscopic study for 1 year and found a positive association between synovitis and progression of medial chondropathy [72]. Symptomatic progression measured in visual analogue score after 1 year was also higher in the group with synovitis (OR 3.11, 95% CI: 1.07–5.69). Inflammation in the form of effusion has also been investigated. Ledingham et al. [44] described synovial fluid volume and nodal warmth in relation to progression of knee OA. For synovial fluid volume as a continuous variable, a significant relationship was found (change in K/L score OR 1.03, 95% CI: 1.01–1.05; change in attrition OR 1.80, 95% CI: 1.00–1.05). With regard to nodal warmth in relation to change in K/L score, a significant relationship was also found (OR 1.80, 95% CI: 1.02–3.17). More recently, ultrasonographic knee effusion has been shown to be predictive of total knee replacement in a 3-year prospective study with an HR of 2.63 (95% CI: 1.70–4.06, p < 0.0001) [74]. MRI There is limited evidence that MRI bone marrow lesions are predictive of OA progression Bone marrow lesions on MRI have been shown to markedly increase the risk of later cartilage loss, particularly in the joint region superficial to the radiological lesion [37]. These lesions are observed to be closely associated with malalignment. When adjusted for malalignment, the relationship of bone marrow lesions with OA progression reduces. Felson et al. [75] found an association between medial bone marrow oedema lesions versus no medial lesions in relation to progression of knee OA (OR 5.6, 95% CI: 2.1–14.8). No association was found between lateral bone marrow oedema lesions versus no lateral lesions in relation to progression.
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Practice points There seems to be strong evidence that malalignment and generalised OA are associated with progression of OA in the knee. There also seems to be strong evidence that sex and knee injury are not associated with the radiologic progression of knee OA. The level of hyaluronic acid in serum is associated with radiologic progression of OA in both knee and hip.
Discussion In this review, only a few significant associations were considered as associated prognostic factors for the progression of OA. We may have been a little conservative in our estimates of association since only well-demonstrated associations were considered here. Furthermore, although we have endeavoured to present a complete and up-to-date review, using both existing reviews and original articles, we may have missed some articles as the subject is largely published. The present review mainly dealt with radiologic progression of OA, and the conclusions cannot directly be applied to clinical progression of OA, whereas for clinical use it is of major interest to know the relationship between these factors and clinical progression of OA. However, because pain and functional status in hip or knee OA seem to deteriorate slowly, with limited evidence for worsening after 3 years of follow-up [3], it is difficult to demonstrate an association with potential predictive factors. In summary, this review not only provides the currently available evidence, but also identifies the lack of data with respect to certain prognostic factors of progression of OA.
Research agenda Future research on the potential prognostic factors of progression of OA is needed. The factors where conflicting associations were found (i.e., gender, BMI, IGF-1, bone mineral density, radiographic severity at baseline, COMP and CTX) especially need to be clarified. Furthermore, several factors were investigated in a single study only and provided limited evidence. To strengthen the evidence, there is a need for further high-quality longitudinal research. Summary of current evidence There is strong-to-moderate evidence for knee malalignment, generalised OA, supero-lateral migration of the femoral head, age, hyaluronic acid levels and atrophic bone response of the hip as risk factors for OA progression. There is limited evidence for adduction moment, nutrition, hyaluronic acid levels, quadriceps strength, nutrition, symptoms at baseline and over time, synovitis and MRI bone oedema as predictors of OA progression. There is inconclusive evidence that oestrogens, genetics and disease duration influence OA progression. There is no evidence to support chondrocalcinosis, running and sports, injury, smoking, depression and anxiety and meniscectomy inds progression of OA.
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Factors affecting radiographic progression of knee osteoarthritis. Ann Rheum Dis 1995;54:53–8. [45] Lohmander LS, Gerhardsson de Verdier M, Rollof J, et al. Incidence of severe knee and hip osteoarthritis in relation to different measures of body mass: a population-based prospective cohort study. Ann Rheum Dis 2009;68:490–6. *[46] Niu J, Zhang Q, Torner J, et al. Is obesity a risk factor for progressive radiographic knee osteoarthritis? Arthritis Rheum 2009;61(3):329–35. [47] Spector TD, Hart DJ, Doyle DV. Incidence and progression of osteoarthritis in women with unilateral knee disease in the general population: effect of obesity. Ann Rheum Dis 1994;53:565–8. [48] Brandt KD, Heilman DK, Slemenda C, et al. Quadriceps strength in women with radiographically progressive osteoarthritis of the knee and those with stable radiographic changes. J Rheumatol 1999;26:2431–7. [49] Sharma L, Dunlop DD, Cahue S, et al. Quadriceps strength and osteoarthritis progression in malaligned and lax knees. Ann Intern Med 2003;138:613–9. [50] Amin S, Baker K, Biu J, et al. Quadriceps strength and the risk of cartilage loss and symptom progression in knee osteoarthritis. Arthritis Rheum 2009;60(1):189–98. [51] Lane NE, Oehlert JW, Bloch DA, Fries JF. The relationship of running to osteoarthritis of the knee and hip and bone mineral density of the lumbar spine: a 9 year longitudinal study. J Rheumatol 1998;25:334–41. [52] McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 1996;125:353–9. [53] McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 1996;39:648–56. [54] Valdes AM, Spector TD. The contribution of genes to osteoarthritis. Med Clin North Am 2009 Jan;93(1):45–66. [55] Valdes AM, Spector TD. The clinical relevance of genetic susceptibility to osteoarthritis. Best Practice and Research in Clin Rheum 2010;24:3–14. [56] Sowers MR, McConnell D, Jannausch M, et al. Estradiol and its metabolites and their association with knee osteoarthritis. Arthritis Rheum 2006;54:2481–7. [57] Zhang Y, McAlindon TE, Hannan MT, et al. Oestrogen replacement therapy and worsening of radiographic knee osteoarthritis in women: the Framingham study. Arthritis Rheum 1998;41:1867–73. [58] Fraenkel L, Zhang Y, trippel SB, et al. Longitudinal analysis of the relationship between serum insulin-like growth factor I and radiographic knee osteoarthritis. Osteoarthr Cartil 1998;6:363–7. [59] Pavelka K, Forejtova S, Olejarova M, Gatterova J. Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis. Osteoarthr Cartil 2004;12(4):277–83. [60] Bruyere O, Collette JH, Ethgen O, et al. Biochemical markers and cartilage remodelling in prediction of long-term progression of knee osteoarthritis. J Rheumatol 2003;30:1043–50. [61]. Sharif M, Shepstone L, Elson CJ, et al. Increased serum C reactive protein may reflect events that precede radiographic progression in osteoarthritis of the knee. Ann Rheum Dis 2000;59:71–4. [62] Sharif M, Saxne T, Shepstone L, et al. Relationship between serum cartilage oligomeric matrix protein levels and disease progression in osteoarthritis of the knee joint. Br J Rheumatol 1995;34:306–10. [63] Hart DJ, Cronin C, Daniels M, et al. The relationship of bone density and fracture to incident and progressive radiographic osteoarthritis of the knee: the Chingford study. Arthritis Rheum 2002;46:92–9. [64] Zhang Y, Hanna MT, Chaisson CE, et al. Bone mineral density and risk incident and progressive radiographic knee osteoarthritis in women: the framingham study. J Rheumatol 2000;27:1032–7. [65] Dieppe P, Cushnaghan J, Tucker M, et al. The Bristol ‘OA500 study’: progression and impact of the disease after 8 years. Osteoarthr Cartil 2000;8:63–8. [66] Dieppe PA, Cushnaghan J, Shepstone L. The Bristol ‘OA 500’ study: progression of osteoarthritis over 3 years and the relationship between clinical and radiographic changes at the knee joint. Osteoarthr Cartil 1997;5:87–97. [67] Hunter DJ, Li J, LaValley M, et al. Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study. Arthritis Res Ther 2007;9:R108. [68] Vilim V, Olejarova M, Machacek S, et al. Serum levels of cartilage oligomeric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis. Osteoarthr Cartil 2002;10:707–13. [69] Bettica P, Cline G, Hart DJ, et al. Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study. Arthritis Rheum 2002;46:3178–84. [70]. 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[73] D’Agostino MA, Conaghan P, Le Bars M, et al. EULAR report on the use of ultrasonography in painful knee osteoarthritis. Part 1: prevalence of inflammation in osteoarthritis. Ann Rheum Dis 2005 Dec;64(12):1703–9. [74] Conaghan P, D’Agostino MA, Le Bars M, et al. Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3 year, prospective EULAR study. Ann Rheum Dis 2009 May 10 [Epub ahead of print]. [75] Felson DT, McLaughlin S, Goggins J, et al. Bone marrow oedema and ist relation to progression of knee osteoarthritis. Ann Intern Med 2003;139:330–6.
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What are the best markers for disease progression in osteoarthritis (OA)? P.P. Cheung, MD, Articulum Research Fellow *, L. Gossec, MD, PhD, Rheumatologist 1, M. Dougados, MD, Professor of Rheumatology Paris Descartes University, Medicine Faculty, UPRES-EA 4058, APHP, Rheumatology B Department, Cochin Hospital, Paris, France
Keywords: osteoarthritis prognosis progression
To be able to prevent progression of osteoarthritis, the knowledge of prognostic factors of this progression is important. If certain prognostic factors are modifiable, they may enhance our ability to reduce osteoarthritis progression. Even if these prognostic factors are not modifiable, they can still be used to identify high-risk groups, which may have implications for patient information and the perspective of medical treatment. Prognostic factors of progression are reviewed here, mainly for hip and knee osteoarthritis as most data available concern these localisations. Areas of further research are highlighted. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Radiographic osteoarthritis (OA) is frequent and potentially debilitating. Due to an ageing population, the prevalence of OA is expected to increase in the next decades [1]. In western countries, the increase in prevalence in the next 20 years is expected to be about 40%, making OA the fourth leading cause of disability [1]. Little is known, however, about the course of disability over time in patients with OA. To optimise the management of OA, it is important to increase our knowledge regarding the predictors of progression of OA. If certain prognostic factors are modifiable, they may enhance our ability to reduce OA progression. Even if they are not modifiable, it can still be used to identify high-risk groups, which
* Corresponding author. Tel.: þ33 1 58412606; Fax: þ33 1 43257884. E-mail addresses: [email protected] (P.P. Cheung), [email protected] (L. Gossec), maxime.dougados@cch. aphp.fr (M. Dougados). 1 Tel.: þ33 1 58412606; Fax: þ33 1 43257884. 1521-6942/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.08.009
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may have implications for patient information and medical treatment [2]. Knowledge about modifiable factors and high-risk groups is also relevant for clinical research, such as studies evaluating therapeutic interventions, including disease-modifying therapies. Objective The objective of this review is to summarise available data pertaining to prediction of OA progression. Some necessary precisions Localisation of OA Although OA is frequent at several locations, that is, the lower limb joints (hip and knee), the spine and the fingers (hand OA), most data regarding prognostic factors of progression are available for hip and knee OA, for which this review concentrates mostly on. How to define progression: symptoms versus X-rays Progression of OA can be assessed through symptoms (i.e., pain and/or functional consequences) [3]. Knowledge of functional consequences is essential for the development of optimal rehabilitation programmes in OA patients. Progression can also be defined through structural progression (generally assessed by radiologic progression on plain radiographs) [4–6]. Scoring techniques used include the Kellgren and Lawrence grading [7], measurement of joint space width (JSW) in millimetres or use of the Osteoarthritis Research Society International (OARSI) atlas [8]. Due to the contradictory association between radiologic OA and functioning [9–11], information about functional course cannot be derived from studies on radiologic progression. Another possible definition of progression is the requirement for total joint replacement, a surrogate marker of more severe spectrum of disease [12]. In this review, we present the available data which relate mostly to predictors of radiographic progression. Differences between data issued from trials and cohorts One of the difficulties is that data available regarding prognostic factors of progression of OA are issued from two main different sources: clinical trials (e.g., the Evaluation of the Chondromodulating Effect of Diacerein in Osteoarthritis of the Hip trial, ECHODIAH [13], a French multicentre randomised controlled trial in hip OA) and epidemiologic cohorts, population based or not (e.g., Hawker et al. [14], a large prospective population cohort study of 2128 individuals studying factors on progression of hip and knee OA with a median follow-up of 6.1 years). As patients participating in clinical trials do not reflect the general population [15], epidemiologic cohort data may be more relevant for clinical practice. However, both types of data are reported here, since many elements have been reported mainly in trials. For the purposes of this review, the current knowledge regarding prognostic factors of progression in OA will be divided into patient and disease characteristics. Part I. Patient characteristics predictive of OA progression The various patient characteristics studied in OA progression and the level of evidence are summarised in Table 1. Age There is moderate evidence that age is a risk factor for hip and knee OA progression Age is a risk factor for occurrence of OA but may not be a risk factor for progression of OA [16,17]. In a 12-year follow-up study of a general population of 239 patients, Schouten et al. [18] found
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Table 1 Patient characteristics and the strength of association in prediction of OA progression. Risk factor
Strength of association
Age Gender Malalignment of the knee Adduction moment of the knee Quadriceps strength Sports and running Nutrition Superolateral migration in hip OA Atrophic bone response in hip Injury and knee OA Meniscectomy and meniscal damage Chondrocalcinosis Obesity Smoking, anxiety and depression Genetics Hormones Insulin Growth Factor 1 Hyaluronic acid Bone mineral density
Moderate Conflicting Strong Limited Limited No evidence Limited to moderate Moderate Strong No relationship No evidence No evidence Conflicting No relationship Inconclusive Inconclusive Conflicting Moderate Conflicting
Strong ¼ majority of available studies showing positive association, Moderate ¼ fewer studies but positive association is shown is majority of these studies, Limited ¼ positive association is shown but there are limited studies, Conflicting ¼ there are positive and negative studies, Inconclusive ¼ there are studies but can neither conclude a positive or a negative association, No relationship ¼ majority of studies show no relationship.
a significant association between age and progression of knee OA, measured by the change in joint space width (JSW). This was only for the comparison of the fourth quartile (higher age) versus the first quartile (lower age) with an odds ratio, OR, of 3.84 (95% confidence interval, CI: 1.10–13.4) in patients over 60 years old. On the other hand, a number of studies found no significant association [19–22]. In hip OA, there appears to be conflicting evidence that age is a risk factor for hip OA progression, although several studies have shown this association [6,23]. Positive studies [13,24,25] such as ECHODIAH [13] analysed 507 patients with symptomatic hip OA. In patients over 65 years old at baseline, there was an OR of 1.9 (95% CI: 1.18–3.08) of having radiological progression of the hip at 12 months. By contrast, Conrozier et al.[26], in a prospective follow-up study of 1 year, found no association between age and OA hip progression measured radiographically (JSW). Hawker et al. [14] studied both hip and knee OA and showed that increased age had an increased hazard ratio (HR) ranging from 1.46 to 1.57 of undergoing total joint arthroplasty. Gender There is conflicting evidence that female sex is associated with progression of OA in the hip and there is no evidence for knee OA progression There is no evidence supporting that female sex is a risk factor for progression of knee OA [18,20–22,27–29]. There is conflicting evidence that female sex is associated with progression of OA in the hip with only one cohort study that reported a positive association. In the ECHODIAH trial [13], a greater proportion of women had more structural progression at 1 year and more women had undergone total hip arthroplasty at 5 years, with an HR of 1.4 (95% CI: 1.1–1.8) [30]. Malalignment of the knee There is strong evidence of varus and valgus malalignment for OA progression of knee Malalignment (either valgus or varus) concentrates loading on a focal area, to the level at which cartilage damage may occur, potentially leading to OA progression. The systematic review by Tanamas
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et al. [31] found that knee malalignment is a strong independent risk factor for progression of knee OA. This was supported in both high-quality radiographic [27,32–34] and magnetic resonance imaging (MRI) cohort studies [35–37]. Three studies [27,33,34] reported a statistically significant association between varus alignment and progression of OA measured by a decrease in JSW. In the study by Miyazaki et al. [27], varus alignment and progression of knee OA had an OR of 3.10, (95% CI: 1.07–9.12) in the univariate analysis, but not multivariate analysis. Cerejo et al. [33] and Miyazaki et al. [27] found a statistically significant relationship with progression of OA when there was valgus malalignment (ORs 10.44 and 4.89, respectively). The third study reported association of OA progression with varus and valgus malalignment (ORs 2.98 and 3.42, respectively) [34]. Adduction moment of the knee There is limited evidence that increase in adduction moment of the knee is a risk factor for progression of OA knee Biomechanical factors such as the adduction moment of the knee have been considered to be an influential factor producing medial joint force in joints with varus deformity with the magnitude correlating with OA disease severity [27,38,39]. The only study examining the risk of high adduction moment to OA progression in the knee investigated 106 patients with medial compartment OA followed up for 6 years [27]. With a 1% increase in adduction moment, the risk of progression was increased by 6.5 times. However, gait analysis systems are not readily available for this risk factor to be useful in clinical practice. Type of migration in hip OA There is moderate evidence of superolateral migration and progression of hip OA In two out of the three highest-quality cohort studies reported in a systematic review [6], a more rapid progression of hip OA was found in patients with a superolateral migration of the femoral head [13,26]. The third high-quality study reported a positive association with superior migration [29]. Atrophic bone response in hip There is strong evidence that atrophic bone response is a risk for hip OA progression From three cohort studies including two of high quality evaluating the association between atrophic bone response and progression of hip OA, all three reported a positive association [26,29,40]. Injury and knee OA There is no association of knee injury and progression of knee OA Cooper et al. [41] studied the relationship between previous knee injury and progression of OA, while Schouten et al. [18] studied the presence of knee injury including sporting injuries at follow-up. Both these studies reported no association. Meniscectomy/meniscal damage and knee OA There is evidence of the prognostic role of meniscal damage and meniscectomy for incident OA of the knee but not for progression of knee OA Studies of meniscal damage on progression of OA have mainly used patients who have undergone meniscectomy. There has been a clear increase in risk of incident OA in patients who have undergone meniscectomy [38]. On the other hand, the evidence for a relationship between meniscectomy and progression of OA is poor [18].
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Chondrocalcinosis There is no evidence for an association between chondrocalcinosis and progression of knee OA A number of cross-sectional studies have found an association between the presence and severity of OA with chondrocalcinosis; however, evidence for radiographic progression on X-rays is lacking. A study evaluating two prospective cohorts on the progression of knee OA using longitudinal MRI assessments of cartilage loss failed to show a positive association [42]. There is also a lack of association when measured by JSW [18]. However, some authors support an association between calcium pyrophosphate and OA progression [43,44]. Weight – body mass index (BMI) There is conflicting evidence that obesity measured by BMI is a risk factor for knee and hip OA progression Although obesity is a strong risk factor for incident (new-onset) tibiofemoral and hip OA [45], findings on the relationship between BMI and OA progression are inconsistent. The data from the Multicentre Osteoarthritis STudy (MOST), an epidemiologic study of knee OA, showed that obesity had no effect on progression in OA knees with varus alignment; however, it did increase the risk of progression in knees with neutral or valgus alignment [46]. In that study, Niu et al. explained that the stress on varus knees might be sufficient by itself to produce progression, and that excess load conferred by obesity may not be necessary as an additional factor. Knees with valgus alignment do not necessarily produce comparable valgus stress. The Rotterdam study, a large population cohort of 3585 patients, showed that a high body mass index (BMI) was associated with progression of knee OA (OR 3.2) but not with hip OA [25]. In the study by Cooper et al. [41], a significant relationship with BMI was only found in the comparison of the highest tertile versus the lowest tertile in the group with baseline K/L grade 2 or higher. Other studies found no statistically significant association [20,27,47]. The relationship between change in BMI and progression of OA was also investigated, but no statistically significant association was found [47]. Quadriceps strength There is no evidence that quadriceps strength is predictive of OA progression in the knee, except for perhaps the lateral compartment of the patellofemoral joint Quadriceps strengthening has been widely recommended for treatment of knee OA, but the impact of quadriceps strength on the course of OA progression is not well understood. Several authors found no difference in baseline quadriceps strength between those with and without OA progression [48,49]. Even when MRI was used as the outcome measure, there was no association between quadriceps strength and cartilage loss at the tibiofemoral joint [50]. In that particular study, quadriceps strength was protective against cartilage loss only at the lateral compartment of the patellofemoral joint with an OR of 0.4 (95% CI: 0.2–0.9) when comparing the highest versus the lowest tertile of strength. Greater quadriceps strength may prevent lateral offset and tilt of the patella, thus protecting against cartilage loss at the lateral compartment of the patellofemoral joint. Despite these findings, maintaining strong quadriceps is of benefit to those with knee OA but more work is needed to determine the type and frequency of exercise regimen that would be beneficial. Sports and running There is no evidence that sports and running increases risk of OA progression, more studies are needed Experimental studies in animals have indicated that running causes relatively little increased risk of OA progression, although it may stimulate osteophyte formation. The effect of sports activity on OA risk depends upon whether the activity was undertaken by a person with an already damaged joint or a normal joint. When protective mechanisms of damaged joints are impaired, it is vulnerable to the trans-articular loading that occurs with sports activity.
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There are limited clinical studies on risk factors in OA progression. There is no significant association between running and progression of OA in three studies [18,41,51]. Nutrition A significant relationship appears to be present between Vitamin D and C concentrations and OA progression, but more studies are needed to confirm this Nutrients may influence OA in at least four ways: protection from excessive oxidative damage, modulation of the inflammatory response, cellular differentiation and biological actions secondary to bone and collagen synthesis. McAlindon et al. [52,53] investigated the relationship between nutrition variables and progression of OA. For vitamin D, a low dietary intake and low serum level were associated with progression of knee OA (OR 4.05, 95% CI: 1.40–11.6 and OR 2.89, 95% CI: 1.01–8.25) for lowest versus highest tertile of dietary intake and serum levels, respectively. Furthermore, for vitamin C intake, a significant association was found (highest versus lowest tertile OR 0.26, 95% CI: 0.11–0.61). A significant association was reported for b-carotene intake only in the comparison of the highest versus the lowest tertile (middle versus lowest OR 1.42, 95% CI: 0.68–3.00). For vitamin E intake, no statistically significant association was found for the highest versus the lowest tertile. No relationship was found with vitamin B1, vitamin B6, niacin and folate. Smoking, anxiety and depression There is no evidence that smoking, anxiety or depression increases progression of OA Very little data have been found to indicate that smoking, anxiety or depression might increase progression of OA [18,22]. Genetics There is inconclusive evidence that genes contribute to OA progression The evidence for the role of genetics is unclear for OA progression, contrary to OA incidence [54]. Please refer to the article on genetics in the present issue for more information [55]. Hormones There is inconclusive evidence that oestrogen is protective of progression of knee OA Of particular interest has been the role of hormones such as oestrogen in the development of OA, largely from the observations of hormone replacement therapy (HRT) on the prevalence and incidence of OA. Oestrogen may have a beneficial effect on the structural progression of OA, particularly in the lower limbs. Lower circulating oestradiol and 2-hydroxyestrone levels have been associated with more prevalent and incident OA (defined radiographically) [56]. However, prospective cohort studies on oestrogen and effects on OA progression are lacking. Zhang et al. [57] investigated the relationship between oestrogen use and radiologic progression of knee OA in a prospective cohort study of 551 women showing current use of HRT had a moderate but non-statistically significant protective effect against progression of knee OA. No significant association was found between current use, and history of oestrogen use and progression of knee OA. Other biology There is conflicting evidence for insulin-like growth factor 1 (IGF-1) and moderate evidence for hyaluronic acid concentration regarding prediction of OA progression There are conflicting reports that insulin-like growth factor 1 (IGF-1) increases risk of OA progression [18,58]. Hyaluronic acid concentration may have a predictive value in knee osteoarthritis progression. This has been indicated in several studies [24,59–62]. Despite this, there are no studies supporting the hypothesis that intra-articular injection of hyaluronic acid would halt progression of OA.
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Bone mineral density There is conflicting evidence that high bone mineral density decreases progression in knee OA and therefore more studies are required Hart et al. [63] in their study on the incidence and progression of knee OA and relationship with bone density reported no statistically significant difference in bone density between the nonprogressive OA group and the progressive OA group. By contrast, Zhang et al. [64] found a minor association between high versus low bone density and progression of knee OA (fourth vs. first quartile OR 0.1, 95% CI: 0.03–0.3). Further studies are needed.
Part II. Disease characteristics The various disease characteristics studied in OA progression and level of evidence are summarised in Table 2.
Symptoms at baseline There is limited evidence that knee pain at baseline can predict OA progression in the knee Three studies found a significant relationship between knee pain at baseline and progression of knee OA [13,20,22].
Progression of symptoms over time There is limited evidence that persistence of symptoms predicts OA progression Dieppe et al.[65,66] reported a statistically significant relationship between the use of non-steroidal anti-inflammatory drugs and an overall measure of change of OA. In addition, Dougados et al. reported the level of pain and functional disability in conjunction with the amount of symptomatic treatment during a 1-year follow-up period explained 20% (p < 0.0001) of the variability in the JSW in the hip [13].
Initial radiographic severity There is conflicting evidence that initial severity of X-ray changes is predictive of OA progression in the knee Concerning severity of OA, only Wolfe and Lane [22] found a significant association between the initial JSW score and progression. Ledingham et al. [44] found a significant association with the change in attrition; in their study, no association was found between radiologic severity and change in the K/L score or JSW. Contradictory associations were found in the relationship between clinical severity and progression of knee OA [22,66].
Table 2 Disease characteristics and the strength of association in prediction of OA progression. Risk factor
Strength of association
Symptoms at baseline Progression of symptoms over time Initial radiographic severity Generalised OA Disease duration Serum COMP UCTX-II Inflammation/Synovitis Bone marrow lesions on MRI
Limited Limited Conflicting Strong Inconclusive Conflicting Conflicting Limited Limited
For explanations please refer to Table 1.
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Generalised OA There is strong evidence that presence of generalised OA is a risk factor for progression in OA of knee Several authors [18,44] reported a significant positive association between the presence of generalised OA (radiologically and/or clinically determined) and progression of knee OA. Disease duration There is inconclusive evidence for the association between length of disease duration and progression for OA Dieppe et al. [20] found no association with the duration of symptoms, and Wolfe and Lane [22] found a borderline significant association. Markers of bone or cartilage turnover There is conflicting evidence that serum cartilage oligomeric matrix protein (COMP) and urinary CTX-II are biomarkers predictive of OA progression There are many biomarkers under investigation potentially predictive of OA progression; however, progress has been slow. The only biomarker shown to be predictive of subsequent MRI-determined cartilage loss in knee OA has been the baseline level of serum COMP [66]. Conflicting reports of COMP are seen with progression determined by X-rays [60,61,68]. In terms of collagen-derived markers, Bettica et al. [69] found a relationship between urinary type I collagen telopeptide (uCTX-I) and progression of knee OA. uCTX-II has also been reported to be a good marker for progression of OA in the knee and hip [24,70,71]. However, uCTX-II has not predicted MRIdetermined cartilage loss [67]. Bruyere et al. [60] found no significant associations between osteocalcin, pyridinoline, or deoxypyridinoline and progression of knee OA. Inflammation There is limited evidence that inflammation (synovitis) is predictive of OA progression in the knee It is clear that synovitis can be present in patients with knee OA [72,73]. Ayral et al. performed a multicentre, longitudinal arthroscopic study for 1 year and found a positive association between synovitis and progression of medial chondropathy [72]. Symptomatic progression measured in visual analogue score after 1 year was also higher in the group with synovitis (OR 3.11, 95% CI: 1.07–5.69). Inflammation in the form of effusion has also been investigated. Ledingham et al. [44] described synovial fluid volume and nodal warmth in relation to progression of knee OA. For synovial fluid volume as a continuous variable, a significant relationship was found (change in K/L score OR 1.03, 95% CI: 1.01–1.05; change in attrition OR 1.80, 95% CI: 1.00–1.05). With regard to nodal warmth in relation to change in K/L score, a significant relationship was also found (OR 1.80, 95% CI: 1.02–3.17). More recently, ultrasonographic knee effusion has been shown to be predictive of total knee replacement in a 3-year prospective study with an HR of 2.63 (95% CI: 1.70–4.06, p < 0.0001) [74]. MRI There is limited evidence that MRI bone marrow lesions are predictive of OA progression Bone marrow lesions on MRI have been shown to markedly increase the risk of later cartilage loss, particularly in the joint region superficial to the radiological lesion [37]. These lesions are observed to be closely associated with malalignment. When adjusted for malalignment, the relationship of bone marrow lesions with OA progression reduces. Felson et al. [75] found an association between medial bone marrow oedema lesions versus no medial lesions in relation to progression of knee OA (OR 5.6, 95% CI: 2.1–14.8). No association was found between lateral bone marrow oedema lesions versus no lateral lesions in relation to progression.
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Practice points There seems to be strong evidence that malalignment and generalised OA are associated with progression of OA in the knee. There also seems to be strong evidence that sex and knee injury are not associated with the radiologic progression of knee OA. The level of hyaluronic acid in serum is associated with radiologic progression of OA in both knee and hip.
Discussion In this review, only a few significant associations were considered as associated prognostic factors for the progression of OA. We may have been a little conservative in our estimates of association since only well-demonstrated associations were considered here. Furthermore, although we have endeavoured to present a complete and up-to-date review, using both existing reviews and original articles, we may have missed some articles as the subject is largely published. The present review mainly dealt with radiologic progression of OA, and the conclusions cannot directly be applied to clinical progression of OA, whereas for clinical use it is of major interest to know the relationship between these factors and clinical progression of OA. However, because pain and functional status in hip or knee OA seem to deteriorate slowly, with limited evidence for worsening after 3 years of follow-up [3], it is difficult to demonstrate an association with potential predictive factors. In summary, this review not only provides the currently available evidence, but also identifies the lack of data with respect to certain prognostic factors of progression of OA.
Research agenda Future research on the potential prognostic factors of progression of OA is needed. The factors where conflicting associations were found (i.e., gender, BMI, IGF-1, bone mineral density, radiographic severity at baseline, COMP and CTX) especially need to be clarified. Furthermore, several factors were investigated in a single study only and provided limited evidence. To strengthen the evidence, there is a need for further high-quality longitudinal research. Summary of current evidence There is strong-to-moderate evidence for knee malalignment, generalised OA, supero-lateral migration of the femoral head, age, hyaluronic acid levels and atrophic bone response of the hip as risk factors for OA progression. There is limited evidence for adduction moment, nutrition, hyaluronic acid levels, quadriceps strength, nutrition, symptoms at baseline and over time, synovitis and MRI bone oedema as predictors of OA progression. There is inconclusive evidence that oestrogens, genetics and disease duration influence OA progression. There is no evidence to support chondrocalcinosis, running and sports, injury, smoking, depression and anxiety and meniscectomy inds progression of OA.
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