Factors Affecting Radiographic Progression of Knee Osteoarthritis

IGINAL ARTICLE Factors Affecting Radiographic Progression of Knee Osteoarthritis Harry Isbagio ABSTRACT Aim: to determine factors affecting radiographic progression of knee OA. Methods: a cross sectional study comprise of patients with OA of knee joints. Kellgren and Lawrence (K-L) grading scale was used to evaluate the radiographic progression of knee OA. All of the patient were noted the demographic data including age, gender, duration of illness, body mass index and bone mass density. Lunar DEXA was used to measure total body-bmd (T-BMD), total bone mineral content (T-BMC) and legs-bmd (L-BMD). Results: about 91 patients was enrolled in this study There were significant differences of body mass index (BMI) (p=0.01) between sub of knee OA grading. between grade 2 and grade 4 for BMI score highest tertile and BMI score lowest tertile were 5.26 (95%CI 0.59-47.20). There were no significant differences for age, sex, and duration of illness, T-BMD, L-BMD and T-BMC between sub of knee OA grading. There were a tendency of correlation on increased of age ( 2.17, 95% CI 0.56-8.41), log-duration of illness, percentage of T-BMD (4 % between grade 2 and 4) with increased of knee OA grading. There was a tendency decrease of percentage of L-BMD (of 7%) between grade 3 and 4. Conclusion: in this cross sectional model, BMI was significantly associated with increased of knee OA grading or it could be said that BMI was risk factors for radiographic progression of OA. Subjects who already have knee OA and also have high BMI must be careful about the progressivity of their knee OA. Key words: knee osteoarthritis, radiographic progression, risk factors,bmi INTRODUCTION Knee osteoarthritis (OA) is one of the major causes of pain and physical disability in elderly 1. A recent World Health Organization report on the global burden of disease indicates that knee OA is likely to become the fourth most important cause of disability in women, and the eighth most important cause in men 2. Several investigations of risk factors for knee OA have been reported previously. Most of them were a cross-sectional studies on disease prevalent, using radiographic criteria to define cases with OA. Some studies have attempted to differentiate between incidence from progression of OA. They have shown that important risk factors for incidence of knee OA could be divided in to systemic and local mechanical injury. The systemic risk factors include etnic 3, age 4, gender 4, obesity 4,5, genetics factors 6,7, nutrition 8, hormon replacement therapy 9, and bone density 10. The local mechanical factors include previous knee injury 11, selected physical activities 12, sports 13, joint alignment 14, joint laxity 15 and proprioseptic 16 As a consequence, much of the emphasis in the development of possible preventive strategies has been on protecting the knee joint from mechanical injury and stress. The risk factors for progression of knee OA include obesity 17, joint effusion 18, joint aligment 19, knee injury 20, and low bone density 21,22. Several strands of indirect evidence suggest that the incidence and progression of radiographic knee OA may involve different processes. The knowledge of risk factors for progression of knee OA make possibility to build a more effective public health strategy that preventing progression to severe joint damage than attempting to prevent the initiation of disease. The objective of this study is to explore several factors affecting radiographic progression of knee OA. Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine of The University of Indonesia- Dr.Cipto Mangunkusumo National Centre Hospital, Jakarta 87

Harry Isbagio Acta Med Indones-Indones J Intern Med METHODS This study is a cross sectional study on a of patients with OA of knee joints. OA of knee joints was diagnosed on the basis of clinical symptoms, physical examination and radiological findings according to the American College of Rheumatology (ACR) Criteria for Classification of OA of the knee. We used Kellgren and Lawrence (K-L) grading scale to evaluate radiographic progression of knee OA 1. Each joint was classified according to a 5-point scale (0 = normal, 1 = doubtful OA, 2 = minimal OA, 3 = moderate OA, 4 = severe OA) based on the degree osteophyte formation, joint space narrowing, sclerosis, and joint deformity. The patients who had grade 0 and 1 were excluded. Informed consent was obtained from all participants. The procedures followed were in accordance with the principles of the Declaration of Helsinki in 1975, as revised in 1983. Data Collection All of the patient were noted the demographic data including age, gender, duration of illness, body mass index which was calculated as the ratio of weight (kg) and the square of height (m), and bone mass density. Bone Mass Density Bone mass density (BMD) was measured by Dual Energy X-ray Absorptiometry (Lunar DEXA, Lunar Corp, Madison, WI) for total body-bmd (T-BMD), total bone mineral content (T-BMC), legs-bmd (L-BMD). Variables The independent variable was the grading scale of radiographic progression of knee OA (K-L grading) of the most severely diseased knee. The dependent variable was the all of the variables noted on demographic data, for the bone mass density included T-BMD, T-BMC, and L-BMD. Statistical Analysis Distribution analysis showed duration of illness were not normally distributed and thus were log transformed to obtain normal distribution before statistical analyses. A comparison of variables between subs of OA knee grading was performed by using Analysis of variance (ANOVA), p values <0.05 were considered significant. RESULTS There were 91-study subject satisfied the inclusion criteria of this study. The majority of the patients were female (69.2 %) and the mean of the age were 59.68 ± 8.03 year. There were 47 patients of knee OA grade 2, 33 patients on grade 3 and 11 patients on grade 4. The mean of duration of illness was 44.11 ± 57.99 months. Most of the patient had high body mass index (overweight and obese). The mean value T-BMD was 1.079 ± 0.1022 g/cm 2, L-BMD was 1.0380 ± 0.1215 g/cm 2, and T-BMC was 8120.59 ± 163.63 g.(table 1) From the ANOVA test, there were significant differences of body mass index (BMI) between sub of knee OA grading (p= 0.01), further explore from this test revealed the significancy was between grade 2 to 4 and grade 3 to 4. This diferences was not significant for age, log duration of illness, T-BMD, L-BMD and T-BMC between sub of knee OA grading (Table 2). From Chi-square test, there was also no significant difference of gender between sub of knee OA grading (Tabel 3). Table 1. Baseline Characteristic of The Subject (n =91) N Mean Standard Deviation Age (years) 91 59.68 8.03 Sex Female Male 63 (69.2%) 28 (30.8%) 2 3 4 Duration of Illness (months) Body Mass Index 47 (51.6%) 33 (36.3%) 11 (12.1%) 78 44.11 57.99 91 25.88 3.85 (kg/m 2 ) T-BMD (g/cm 2 ) 91 1.0790.1022 L-BMD (g/cm 2 ) 44 1.0380.1215 T-BMC (g) 90 810.59 163.63 If the patient was devided into 2 according to their age with the cutt off point of 60 years, where the patient with the age < 60 years as one and ³ 60 years as the another, calculation of the odds ratio () between grade 2 versus grade 3 (equal with increased 1 grade) revealed 1.68 (95% CI 0.68-4.13), and grade 2 versus grade 4 ( equal with increased 2 grade) was 2.17 (95% CI 0.56-8.41). Although the differences between those sub was not significant, there was a tendency increased of (Tabel 4). Odds ratio for gender between sub of knee OA revealed for grade 2 versus grade 3 was 1.77 (95% CI:0.65-4.13) and for grade 2 versus grade 4 was 1.55 (95% CI 0.35-3.47). There was no tendency increased of between those sub (Tabel 5). If the patient was divided into 3 of BMI as follows : BMI < 22.7 kg/m 2 as lowest, BMI ³ 22.7-88

Vol 36 Number 2 April-June 2004 Factors Affecting Radiographic Progression of Knee Osteoarthritis Table 2. A Comparison of Age, Duration of Illness, Body Mass Index, Total-Bone Mass Density, Legs-Bone Mass Density, Total-Bone Mineral Content Between Sub of Knee OA Age (years) 58.34 Log Duration of Illness (months) Body Mass Index (kg/m 2 ) T-BMD (g/cm 2 ) L-BMD 25.4 kg/m 2 as middle, and BMI >25.4 kg/m 2 as highest. Calculation for between grade 2 versus 3 (increased 1 grade) for the lowest to highest was 1.12 (0.36-3.49), and between grade 2 versus grade 4 (increased 2 grade) for the lowest to highest was 5.26 (0.59-47.20), there was a tendency increase of 5 times between those sub (tabel 6). Table 5. Odd Ratio for Gender Between Sub of Knee OA Risk Comparison between sub of knee OA Factor 2 versus 3 2 versus 4 Gender 2 3 Male 17/25 8/25 Referent Female 30/55 25/55 1.77 (0.65-4.78) 2 3 4 p ± 8.52 1.1334 ±0.6027 25.3773 ±3.2885 1.07717 ±0.10759 1.01852 (g/cm 2 ) ±0.12785 T-BMC (g) 812.70 ±163.56 60.58 ± 6.80 1.3715 ±0.6562 25.5270 ±4.2970 1.06985 ±0.092908 1.07682 ±0.098468 790.69 ±126.15 Grad e.2/ Total 17/2 0 30/3 8 62.73 ± 8.76 1.4412 ±0.6410 29.1245 ±0.3919 1.11400 ±0.10674 0.99180 ±0.15136 859.45 ±163.63 ANOVA : * Significant between grade 2 to 4 and grade 3 to 4 Table 3. A comparison of Gender Between Sub of Knee OA 3 2 4.4 0.193 0.193 0.010 * 0.461 0.224 0.486 Total n 30 25 8 63 Sex Female % 63.8 75.8 72.7 69.2 n 17 8 3 28 Male % 36.3 24.2 27.4 30.8 n 47 33 11 91 Total % 100 100 100 100 Chi square test: (P = 0.505) Table 4. Odd Ratio for Age Between Sub of Knee OA Risk Comparison between sub of knee OA Factor 2 versus 3 2 versus 4 Age (years) < 60 years 60 years 2 3 26/40 14/40 Referent 21/40 19/40 1.68 (0.68-4.13).2.4 26/30 4/30 Referent 21/28 7/28 2.17 (0.56 8.41) 3/20 Referent 8/38 1.51 (0.35 3.47) Although there was no significant differences between the mean of log duration of illness between sub of knee OA, but from figure 1. there were a tendency to show a correlation between increased of grade knee OA with log duration of ilness. From figure 2 which was used the percentage of value of total-bmd to the BMD of young adults, there is also a tendency of correlation between increased of BMD percentage with increased of the grade of knee Table 6. Odd Ratio for BMI Between Sub of Knee OA Risk Comparison between sub of knee OA Factor 2 versus 3 2 versus 4 BMI (kg/m 2 ) Lowest (<22.7) Highest (>25.4) OA, especially from grade 3 to grade 4.The difference between grade 2 and grade 4 was about 4 %. It also a surprise if we looked for the percentage legs BMD in figure 3, there was a tendency decrease of BMD between grade 3 and grade 4. The difference was about 7 %. Mean Log duration of illness 1.5 1.4 1.3 1.2 1.1 1.0 2 Figure 1. Bar Diagram of Mean Log Duration of Illness Between Sub of Knee OA DISCUSSION 3/ Total 2 10/18 8/18 Referent 19/36 17/36 1.12 (0.36-3.49) 3.2.4 4 Aged cartilage has altered chondrocyte function and material properties and responds differently to cytokine and growth factors. In a longitudinal study of the Chingford population (women, mean age of 45 years), belonging to the highest of three age s was associated with an increased risk of incident of knee OA (, 2.41; 95%CI, 1.11 to 5.24) after adjustment for hysterectomy, ERT, smoking, physical activity, pain, 10/11 1/11 Referent 19/29 10/29 5.26 (0.59 47.20) 89

Harry Isbagio Acta Med Indones-Indones J Intern Med Mean % Total-BMD to young adult Figure 2. Bar Diagram of Mean % of Total BMD to Young-adult Between Sub of Knee Osteoarthritis Mean % Legs-BMD to young adult 100 98 96 94 92 90 88 99 98 97 96 95 86 2 2 3 3 4 4 Figure 3. Bar Diagram of Mean % of Legs BMD to Young-adult Between Sub of Knee Osteoarthritis social class, height, and weight. 4 Knee osteophyte development increased by 20% per 5-year age increase. Age did not affect the risk of incident of knee OA in longitudinal Framingham study in which the mean age of subjects at baseline evaluation was 70.5 years 23. Only 2 longitudinal studies from several studies was confirmed the influence of age on the radiographic progression of knee OA, it was study from Schouten et al 24 ( 3.8; 1.1 to 13.4) and Ledingham et al 18 ( 1.18; 1.01 to 1.14). In our study although there were no significant influence of age on progression of knee OA in ANOVA test, the for increased of 2 grades was nearly twice with increased of 1 grade. This finding showed the possibility of influence of age on progression of the disease, but it must be careful to make an interpretation, because this study was a cross-sectional study. The influenced of gender on knee OA development may be mediated through multiple routes, including hormonal influences on cartilage metabolism, gender variation in the consequences of injury, gender differences in the mechanical environment of the knee (e.g. varus-valgus laxity) 15. Our study confirmed with other longitudinal study that women develop knee OA more frequently 23. Although gender was confirmed as risk factor for incident of the knee OA, there were no studies found the effect of gender on progression of knee OA, the previous study demonstrate similar findings with our result. There were no longitudinal studies that explore the impact of duration of illness on incident and progression of knee OA. Only one study found that patient underwent Total Knee Replacement (TKR) began symptom of knee OA 16 years before TKR. Patient underwent TKR was 2 years older than those undergoing Total Hip Replacement (THR). Men developed symptom of knee OA an average of 5 yr before women. 25. Our finding found that the duration of illness was not affect the radiographic progression of OA, although there was a tendency correlation between those factors. In our opinion, it is still needed another longitudinal study to confirm such finding. A subsequent Framingham study (mean age of subjects, 70.5 years) in subjects free of disease at baseline assessment confirmed that higher BMI increased the risk of incident of OA (, 1.6 per 5-unit increase; 95% CI, 1.2 to 2.2) and weight change was directly correlated with risk of OA (, 1.4 per 10-pound change in weight) 23. In a longitudinal study of the Chingford population, belonging to the top BMI tertile was associated with an increased risk of incident of knee OA (, 2.38; 95% CI 1.29 to 4.39) 4. There were some study confirmed the influence of BMI on progression of knee OA. Study conducted by Schouten et al 24 found that the between fourth vs. first quartile was 11.1 (3.3 to 37.3), Spector et al 17 found over one third of middle aged women with unilateral disease will progress to bilateral knee OA within 2 years. Cooper et al 26 found that BMI influenced the radiographic progression of knee OA, BMI middle (22.7 25.4 kg/m 2 ) will give 2.3 (0.8-6.4) compare to lowest BMI (<22.7 kg/ m 2 ). BMI Highest (>25.4 kg/ m 2 ) will give 2.6 (1.0-6.8) compare to lowest BMI. Our finding similar with those studies, BMI was significantly associated with the increased of knee OA grading, especially between grades 2 to 4, with the 5.26 for the BMI highest 90

Vol 36 Number 2 April-June 2004 Factors Affecting Radiographic Progression of Knee Osteoarthritis tertile compare to the BMI lowest tertile.we concluded that BMI was risk factors for radiographic progression of OA. Radin et al 27 postulated that increased bone mass and thickening of the subchondral bone plate would cause stiffening of the bone, as a consequence, result in cartilage destruction on repeated loading. In a normal healthy joint, it is postulated that the bone assist in high load tolerance by deformation and the formation of micro fractures, but as it thickens the shock absorbing capacity is reduced and shears stresses increase in the articular cartilage, eventually leading to cartilage fibrillation. Both the Framingham and Chingford study have found that subjects with the knee OA have 5% to 10% higher BMD than those without knee OA 28,29. In the Framingham study, women with K-L grade1 and 2 of the knee had 5% to 9% higher femoral neck BMD than did those with K-L grade O, with adjustment for age, BMI and smoking 29. Women in the Chingford study with knee OA had 7.6% and 6.2% higher BMD at lumbar spine and femoral neck sites, respectively, than did control subjects, with adjustment for age and BMI 28. A recent prospective study has confirmed this relationship by showing a higher bone density increases the risk of incident radiographic knee OA in older women 22. On the other hand Chingford longitudinal study found that among women who already have knee OA, those with low BMD and who are losing bone faster exhibit more rapid progression of radiographic changes than those with high BMD and who are losing bone more slowly 21, confirming the previous finding from the Framingham prospective study 22. With ANOVA test, this study do not find any significant correlation between T-BMD, L-BMD and T-BMC with the radiographic progression of knee OA, but there a tendency increased of percentage of BMD between grade 2 and 4, the difference was about 4 %. This finding was rather different with other study. On the other hand the tendency of decreased of percentage legs-bmd between grade 3 and 4 was support the theory that patient with low BMD would have more rapid progression of knee OA. Dequeker et al 30 tried to explain this situation and said that the increased loss of bone in this location due to local disability of the joint. This study was a cross sectional study which some of the variables (e.g. T-BMD, T-BMC and L-BMD) were not statistically different between sub of K-L grading of knee OA, a longitudinal study was needed to confirm this result. 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