Associations of Metabolic Syndrome and Its Components with the Risk of Incident Knee Osteoarthritis Leading to Hospitalization: A 32-Year Follow-up Study

Abstract

Objectives

To examine whether metabolic syndrome or its individual components predict the risk of incident knee osteoarthritis (OA) in a prospective cohort study during a 32-year follow-up period.

Design

The cohort consisted of 6274 participants of the Mini-Finland Health Survey, who were free from knee OA and insulin-treated diabetes at baseline. Information on the baseline characteristics, including metabolic syndrome components, hypertension, elevated fasting glucose, elevated triglycerides, reduced high-density lipoprotein, and central obesity were collected during a health examination. We drew information on the incidence of clinical knee OA from the national Care Register for Health Care. Of the participants, 459 developed incident knee OA. In our full model, age, gender, body mass index, history of physical workload, smoking history, knee complaint, and previous injury of the knee were entered as potential confounding factors.

Results

Having metabolic syndrome at baseline was not associated with an increased risk of incident knee OA. In the full model, the hazard ratio for incident knee OA for those with metabolic syndrome was 0.76 (95% confidence interval [0.56, 1.01]). The number of metabolic syndrome components or any individual component did not predict an increased risk of knee OA. Of the components, elevated plasma fasting glucose was associated with a reduced risk of incident knee OA (hazard ratio 0.71, 95% confidence interval [0.55, 0.91]).

Conclusions

Our findings do not support the hypothesis that metabolic syndrome or its components increase the risk of incident knee OA. In fact, elevated fasting glucose levels seemed to predict a reduced risk.

Introduction

Osteoarthritis (OA) is a chronic, progressive, and degenerative disease of the joints, also characterized by abnormal remodeling of joint tissues.^1,2 In 2 Finnish health surveys conducted among participants aged over 30 years, knee OA was diagnosed among 5% to 6% of men and 7% to 8% of women.^3,4 In the knee, local biomechanical factors such as obesity, knee malalignment, knee laxity, joint dysplasia, injuries affecting the articular surfaces, tears of menisci or ligaments, decreased proprioceptive accuracy, muscle weakness, occupational loading factors, and excessive loading during leisure time physical activities are widely accepted as predisposing factors for OA.^1,2 The role of systemic factors in the risk of knee OA has been studied with growing intensity. The evidence of the role of nutritional factors such as serum vitamin D status, dietary magnesium, and vitamin C intake, as well as hormonal status in the risk of knee OA is still controversial.^2,5-8

Metabolic syndrome is constituted by insulin resistance, visceral adiposity, dyslipidemia, and elevated blood pressure. It is a cluster of different conditions associated with an increased risk of endothelial dysfunction, prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, reproductive disorders, cardiovascular disease including coronary heart disease, and type 2 diabetes mellitus, as well as all-cause mortality.^9,10 It has been hypothesized that metabolic syndrome and its individual components affect the pathogenesis of knee OA. The methods of previous studies have been diverse in terms of the covariates and endpoints they have included, and some studies have not adjusted for body mass index (BMI).^11-20 Many studies have found that having metabolic syndrome is associated with an increased likelihood of knee OA, but this connection has attenuated after adjustment for BMI.^11-14,21 The previous results concerning individual metabolic syndrome components and their predictive ability of knee OA are controversial.^5,11-20

Given the conflicting results of previous studies, the objective of this study was to assess the association between metabolic syndrome and its individual components and incident clinical knee OA in a longitudinal setting over a 32-year follow-up period.

Materials and Methods

Study Sample and Design

The present prospective cohort study is based on the Mini-Finland Health Survey, which was carried out in Finland between 1978 and 1980. ²² The nationally representative population sample was formed using a 2-stage stratified cluster sampling method, and participants were drawn from the population register of the adult population aged 30 years or over, living in mainland Finland. A more detailed description of the study population and design has been published elsewhere.^23,24

In the first stage, 40 representative areas were selected. In the second stage, a systematic sample of inhabitants was drawn from each area. The sample consisted of 8,000 people (3,637 men and 4,363 women) aged 30 years or over. Of the sample, 90% participated in the comprehensive health examination. Of all the 7,217 participants of the Mini-Finland Health Survey, 782 had knee OA at the baseline examination, 39 had been hospitalized for knee OA before the examination, 63 were on insulin medication, and 113 had missing data in any necessary determinant. A total of 943 participants met one or more of the aforementioned exclusion criteria. The cohort of the current study included 6,274 participants who were followed up until December 31, 2010.

The Mini-Finland Health Survey was carried out before the current legislation on medical research of human subjects became effective. The participants were fully informed of the use of the collected data for research purposes and participated on a voluntary basis in compliance with the principles of the World Medical Association (WMA) Declaration of Helsinki. Agreeing to participate in the baseline health examination was taken to indicate informed consent. The planning, conduct and reporting are in accordance with the International Committee of Medical Journal Editors (ICMJE) recommendations for the protection of research participants.

Baseline Health Examination

The baseline screening examination consisted of questionnaires and symptom interviews. A clinical examination including medical history, symptom history, and physical status was performed 3 to 6 months later at a mobile clinic. ²³ Baseline diagnosis of knee OA was based on a standardized clinical examination. Specially trained physicians performed the physical examinations according to detailed written instructions with uniform diagnostic criteria. The examination covered medical history, symptom history, and limitations in the range of motion, tenderness, deformations, joint effusion, and stability of the knee joint. In brief, prevalent knee OA was diagnosed if some of the following conditions were fulfilled: (1) previous knee arthroplasty, even in the absence of convincing evidence of the diagnosis of knee OA; (2) typical knee OA symptoms and either of the following (even in the absence of abnormality in physical status): history of previously diagnosed knee OA (even in the absence of documentation), or documented knee OA diagnosis even in the absence of convincing evidence of the diagnosis; or (3) limitation in joint range of motion, motion tenderness, and bony deformity suggesting knee OA, but insufficiently indicative history to enable a conclusive diagnosis. The clinical examination and criteria of knee OA have been previously described in detail.^3,7,23,24 The final diagnosis of knee OA was made based on disease history, symptoms, and clinical findings. The agreement between the clinical and radiological diagnosis of knee OA was moderate. ²⁵ Knee complaint was defined as difficulty in walking or limping due to discomfort or trouble in the knee during the previous month. This information was acquired via a standardized interview on musculoskeletal symptoms. ³

Information on socioeconomic background, symptoms, diseases, medications, and lifestyle at baseline was collected via questionnaires and interviews. Smoking was classified into 3 groups based on self-reported information on smoking habits: (1) never smoked, (2) ex-smoker, and (3) current smoker. History of physical workload was classified into 6 categories on the basis of the questionnaire responses: (1) light sedentary work, (2) other sedentary work, (3) physically light standing work or light work involving movement, (4) fairly light or medium heavy work involving movement, (5) heavy manual work, and (6) very heavy manual work. For this study, a history of physical workload was dichotomized into physical work—classes 3 to 6—and no physical work—classes 1 and 2.

Traumatic knee injury was defined as a previous distension of the knee, meniscal tear or rupture of the cruciate ligament, or a femoral or tibial fracture of the knee region. A physician classified the injuries after the baseline examination according to the International Classification of Diseases 8th revision based on all information available in the medical history, symptoms, and physical findings of the clinical examination. The injuries were only accounted for if they had led to permanent damage or to any continuing impairment or complaint.

At the baseline examination, height and weight were measured and BMI (kg/m²) was calculated. We classified the participants into 3 groups by BMI: (1) normal or below normal weight, <25.0 kg/m²; (2) overweight, 25.0 to 29.9 kg/m²; and (3) obese, >30 kg/m².

Overnight (minimum 11 hours) fasting blood samples were taken and stored at −20°C. These samples were analyzed and serum total cholesterol concentrations were determined a few weeks after the samples were taken, using a modified version of the direct Liebermann-Burchard method without serum-blank subtraction (Boehringer, Mannheim, Germany). Fasting serum samples taken during the baseline health examination were kept frozen at −0°C until 2003, when 25(OH)D levels were determined by radioimmunoassay (DiaSorin, Inc., Stillwater, MN). Serum insulin was measured from the stored samples between 2002 and 2003, using a modified version of Herbert’s immunoassay method (microparticle enzyme immunoassay; Insulin kit (REAGENT): Abbott Laboratories, Dainabot, Tokyo, Japan; Analyzer: ABBOT, IMX 20238). Insulin resistance was evaluated by the Homeostatic Model Assessment of Insulin Resistance. ²⁶

Baseline Data of Metabolic Syndrome and Its Components

Our definition of the metabolic syndrome was based on the harmonized definition of the metabolic syndrome. ⁹ The criterion for metabolic syndrome was the presence of any 3 or more of the following 5 components: central obesity, elevated mean blood pressure (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive medication), elevated serum triglycerides (≥1.7 mmol/L), reduced serum high-density lipoprotein (HDL) level (<1.3 mmol/L among women and <1.0 mmol/L among men), and elevated plasma fasting glucose (≥5.6 mmol/L, or diagnosed type 2 diabetes without insulin therapy). For the purposes of this study, we excluded diabetics with insulin therapy at baseline.

Since the present data did not include information on waist circumference, we used the ratio of subscapular to triceps skinfold as an indicator of central versus peripheral distribution of body fat. ²⁷ Trained technicians measured skinfold thicknesses on the right side of the body using a Harpenden skinfold caliper (British Indicators Ltd, John Bull). The subscapular skinfold was measured at the inferior angle of the scapula. The triceps skinfold was measured posteriorly at the halfway point between the outer edge of the acromion process and the olecranon process of the ulna. The highest quintile of the ratio (>1.23) was considered to represent truncal adiposity in the present study. This cutoff was chosen on the basis of the knowledge on the prevalence of central obesity in Finland in 1987. ²⁸

We measured casual blood pressure twice at 90-second intervals using the auscultatory method. As described above, overnight fasting blood samples were taken and stored at −20°C. These samples were analyzed and serum HDL cholesterol, plasma fasting glucose, and serum triglycerides concentrations were determined a few weeks after the samples were taken. We analyzed serum HDL level using Mg-dextrane sulfate precipitation and determined serum triglyceride concentration using the fully enzymatic method (Boehringer, Mannheim, Germany). Plasma fasting glucose was determined using a glucose oxidase method (Boehringer, Mannheim, Germany).

Follow-up Information on Incident Knee OA

We drew the follow-up information on the incidence of knee OA from the national Care Register for Health Care. Patients treated in hospital with a diagnosis of knee OA were identified using the International Classification of Diseases, until 1986 with code 713.01 of the 8th revision, from 1987 until 1995 with code 7151F or 7152F of the 9th revision, and from 1996 onwards with code M17 of the 10th revision. Prior to 1995, the register contained data on patients discharged from inpatient care in hospitals only. From 1995 onwards, diagnoses given in day surgery and specialized outpatient care were also recorded. The follow-up period started from the baseline examination in 1978 to 1980 and continued until the first hospitalization for knee OA, death, or the end of 2010, whichever came first. The register data on all the participants of the study was retrieved from the Care Register for Health Care using their social security number. Record linkage of national health registers to the survey data was approved by the register authorities.

Statistical Analysis

We used Cox’s proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident knee OA according to the categories of the variables of interest: the presence of metabolic syndrome, the 5 components of metabolic syndrome (elevated blood pressure, elevated fasting glucose, elevated triglycerides, reduced HDL cholesterol, and central obesity, the cutoff values of which are described above), and the number of present components of the metabolic syndrome. We first estimated HRs adjusted for age and gender only. Then, we constructed 3 main models: a basic model adjusted for age, gender, and BMI with each variable of interest entered one by one; a full model in which the histories of physical workload and smoking, and difficulty walking due to disorders or complaints in the knees, and previous injury of the knee were also entered as potential confounding factors; and a full model from which the first 15 years of the follow-up was excluded to examine the effect of the possible preclinical disease phase. We selected the potential confounding factors in the full model from those available on the basis of prior assumptions of determinants of knee OA and metabolic syndrome and its components, of which age, gender, BMI, history of physical workload, and knee injuries are major risk factors for knee OA.^2,29,30 We studied the effect modification by entering all the multiplicative first-degree interaction terms of the potential risk determinants, one by one, into the full model. Likelihood ratio statistics were used to test the statistical significance of the interactions. We used the SAS System for Windows, version 9.1 (SAS Institute, Inc., Cary, NC) for all the analyses.

Results

Table 1 shows the baseline characteristics of the participants with and without incident knee OA leading to hospitalization. During the follow-up of 157,987 person-years, 459 participants developed clinical knee OA. Of the incident knee OA cases, significantly more were female, overweight or obese, nonsmokers, and had a history of heavy physical work and knee injuries, current knee complaints, metabolic syndrome, and higher serum 25(OH)D concentrations. The mean age of the group that did not develop incident knee OA during follow-up was higher. The mean levels of serum total cholesterol, plasma fasting glucose, and systolic blood pressure were lower among the participants who developed incident knee OA. Mean triceps skinfold thickness, subscapular skinfold thickness, and subscapular per triceps skinfold ratio were higher among those who developed incident knee OA than among those who did not.

Table 1.

Baseline Characteristics of Participants Free from Knee OA at Follow-up and Incident Knee OA Cases, Mini-Finland Health Survey, 1978 to 1980.

Factor	Participants Free from Knee OA at Follow-up	Incident Knee OA Cases
Number of participants	5,815	459
Age, years
30-44	41.4%	52.7%
45-54	22.9%	30.1%
55-98	35.7%	17.2%
Gender
Male	49.9%	37.9%
Female	50.1%	62.1%
BMI, kg/m2
<25.0	49.6%	33.8%
25.0-29.9	37.9%	46.2%
≥30.0	12.5%	20.0%
Smoking
Never	52.4%	62.5%
Ex-smoker	21.8%	20.3%
Current	25.7%	17.2%
Physical work	51.4%	68.2%
Knee complaints	7.5%	12.4%
Knee injury	1.7%	4.4%
Diabetes (without insulin therapy)	4.1%	1.5%
Antihypertensive medication	12.3%	9.6%
Treatment for dyslipidemia	1.3%	0.4%
Metabolic syndrome	19.2%	12.0%
Number of metabolic syndrome components
0	13.5%	17.2%
1	37.6%	41.4%
2	30.1%	29.4%
3	14.4%	10.5%
4	4.1%	1.5%
5	0.3%	0%
Age, years, mean	49.9 (± SD 13.8)	44.8 (± SD 10.0)
BMI, kg/m2, mean	25.5 (± SD 3.86)	26.9 (± SD 3.86)
Fasting serum 25(OH)D, nmol/L, mean	43.4 (± SD 19.7)	46.3 (± SD 20.0)
Fasting serum total cholesterol, mmol/L, mean	6.92 (± SD 1.38)	6.73 (± SD 1.15)
Fasting serum HDL, mmol/L, mean	1.70 (± SD 0.41)	1.72 (± SD 0.38)
Fasting plasma glucose, mmol/L, mean	5.35 (± SD 1.11)	5.14 (± SD 0.54)
Fasting serum triglycerides, mmol/L, mean	1.50 (± SD 1.06)	1.33 (± SD 0.64)
HOMA-IR, mean	2.09 (± SD 2.09)	1.97 (± SD 1.10)
Systolic blood pressure, mmHg, mean	145 (± SD 23.5)	139 (± SD 18.6)
Diastolic blood pressure, mmHg, mean	87.0 (± SD 11.8)	86.1 (± SD 10.2)
Triceps skinfold, mm, mean	16.5 (± SD 6.95)	19.4 (± SD 7.38)
Subscapular skinfold, mm, mean	15.4 (± SD 7.01)	17.6 (± SD 7.47)
Subscapular per triceps skinfold ratio, mean	0.99 (± SD 0.39)	0.96 (± SD 0.33)

OA = osteoarthritis; BMI = body mass index; SD = standard deviation; 25(OH)D = 25-hydroxyvitamin D; HDL = high-density lipoprotein; HOMA-IR = Homeostatic Model Assessment of Insulin Resistance.

Table 2 shows the HRs and their 95% CIs for incident knee OA leading to hospitalization, according to age, gender, presence of metabolic syndrome, number of metabolic syndrome components, and individual components, as both unadjusted and adjusted for age and gender. Elevated plasma fasting glucose levels predicted a reduced risk of knee OA: the HR (95% CI) for knee OA was 0.75 (0.58-0.97) for those with elevated plasma fasting glucose concentrations in comparison to those without. The HRs for metabolic syndrome and its other components remained nonsignificant.

Table 2.

Hazard Ratios and Their 95% Confidence Intervals for Incident Knee OA Leading to Hospitalization in Categories of Metabolic Syndrome, Each of Its Individual Components, and Number of Metabolic Syndrome Components as Unadjusted and Adjusted for Age and Gender.

	N	n	Unadjusted, HR (95% CI)	Adjusted for Age and Gender, HR (95% CI)
Age, years
30-44	2,651	242	1	1
45-54	1,468	138	1.29 (1.04-1.59)	1.27 (1.03-1.57)
55-98	2,155	79	1.16 (0.89-1.50)	1.11 (0.86-1.45)
Gender
Male	3,074	174	1	1
Female	3,200	285	1.37 (1.13-1.66)	1.36 (1.13-1.64)
Central obesity a
No	5,028	372	1	1
Yes	1,246	87	0.99 (0.78-1.24)	1.17 (0.91-1.51)
Elevated mean blood pressure b
No	1,296	105	1	1
Yes	4,978	354	1.22 (0.98-1.52)	1.22 (0.97-1.53)
Elevated plasma fasting glucose c
No	4,708	388	1	1
Yes	1,566	71	0.75 (0.58-0.97)	0.75 (0.58-0.97)
Elevated serum triglycerides d
No	4,554	359	1	1
Yes	1,720	100	1.03 (0.82-1.28)	1.05 (0.84-1.32)
Reduced serum HDL cholesterol e
No	5,909	439	1	1
Yes	365	20	1.02 (0.65-1.59)	0.96 (0.61-1.51)
Metabolic syndrome f
No	5,125	404	1	1
Yes	1,149	55	0.92 (0.69-1.22)	0.97 (0.73-1.29)
Number of metabolic syndrome f components
0	863	79	1	1
1	2,379	190	1.10 (0.85-1.43)	1.11 (0.85-1.45)
2	1,883	135	1.14 (0.86-1.50)	1.19 (0.89-1.60)
3	886	48	1.08 (0.75-1.54)	1.18 (0.81-1.72)
4	243	7	0.74 (0.34-1.60)	0.80 (0.37-1.76)
5	20	0
Number of metabolic syndrome f components
Increment by one component			1.00 (0.91-1.10)	1.02 (0.93-1.13)

OA = osteoarthritis; N = number of participants in respective category; n = number of disease cases in respective category; HR = hazard ratio; CI = confidence interval; HDL = high-density lipoprotein.

^aSubscapular to triceps skinfold ratio >1.23.

^bSystolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive medication.

^cConcentration ≥5.6 mmol/L or diagnosed type 2 diabetes without insulin therapy.

^dConcentration ≥1.7 mmol/L.

^eConcentration <1.3 mmol/L in women and <1.0 mmol/L in men.

^fDefined as presence of any 3 or more of following 5 components: systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive drug treatment, serum triglycerides ≥1.7 mmol/L, serum HDL cholesterol <1.3 mmol/L among women and <1.0 mmol/L among men, plasma fasting glucose ≥5.6 mmol/L, and subscapular to triceps skinfold ratio >1.23.

Table 3 shows the adjusted HRs and their 95% CIs for incident knee OA leading to hospitalization. After adjustment for age, gender, and BMI, the HR for incident knee OA was 0.83 (95% CI [0.59, 1.15]) for those with baseline metabolic syndrome. After adjustment for all covariates, the HR for incident knee OA was 0.76 (95% CI [0.56, 1.01]) for those with metabolic syndrome at baseline.

Table 3.

Adjusted Hazard Ratios and Their 95% Confidence Intervals for Incident Knee OA Leading to Hospitalization in Categories of Its Major Risk Factors, Potential Confounding Factors, Metabolic Syndrome, Each of Its Individual Components, and Number of Metabolic Syndrome Components.

	N	n	Basic Model, a HR (95% CI)	Full Model, b HR (95% CI)	Full Model, b First 15 Years of Follow-up Excluded
					N	n	HR (95% CI)
Age, years
30-44	2,651	242	1	1	2,504	206	1
45-54	1,468	138	1.08 (0.87-1.34)	1.07 (0.86-1.33)	1,262	108	1.02 (0.80-1.30)
55-98	2,155	79	0.89 (0.68-1.16)	0.91 (0.69-1.21)	1,099	40	0.69 (0.48-0.99)
Gender
Male	3,074	174	1	1	2,253	137	1
Female	3,200	285	1.45 (1.20-1.76)	1.32 (1.05-1.66)	2,612	217	1.29 (1.00-1.67)
BMI, kg/m2
<25.0	3,041	155	1	1	2,412	126	1
25-29.9	2,417	212	2.06 (1.67-2.55)	2.04 (1.64-2.54)	1,876	158	1.98 (1.55-2.53)
≥30.0	816	92	3.07 (2.36-3.99)	3.14 (2.37-4.17)	577	70	3.32 (2.44-4.56)
Smoking
Never	3,336	287	1	1	2,671	219	1
Ex-smoker	1,362	93	0.92 (0.69-1.22)	0.89 (0.69-1.15)	1,023	72	0.90 (0.68-1.20)
Current	1,576	79	0.76 (0.57-1.02)	0.76 (0.58-0.99)	1,171	63	0.78 (0.58-1.05)
Physical work
No	2,971	146	1	1	1,929	104	1
Yes	3,303	313	1.31 (1.06-1.68)	1.29 (1.05-1.57)	2,936	250	1.31 (1.04-1.66)
Knee complaints
No	5,781	402	1	1	4,537	320	1
Yes	493	57	1.49 (1.04-2.13)	1.68 (1.24-2.27)	328	34	1.34 (0.91-1.96)
Knee injury
No	6,158	439	1	1	4,790	341	1
Yes	116	20	2.76 (1.57-4.84)	2.21 (1.36-3.61)	75	13	2.28 (1.25-4.17)
Central obesity c
No	5,028	372	1	1	3,904	286	1
Yes	1,246	87	0.95 (0.71-1.27)	0.94 (0.72-1.21)	961	68	0.93 (0.70-1.25)
Elevated mean blood pressure d
No	1,296	105	1	1	1,169	82	1
Yes	4,978	354	1.09 (0.84-1.41)	1.02 (0.80-1.28)	3,696	272	1.11 (0.85-1.44)
Elevated plasma fasting glucose e
No	4,708	388	1	1	3,811	301	1
Yes	1,566	71	0.74 (0.55-0.99)	0.71 (0.55-0.91)	1,054	53	0.73 (0.54-0.98)
Elevated serum triglycerides f
No	4,554	359	1	1	3,720	284	1
Yes	1,720	100	0.78 (0.59-1.02)	0.86 (0.68-1.09)	1,145	70	0.82 (0.62-1.08)
Reduced serum HDL cholesterol g
No	5,909	439	1	1	4,635	339	1
Yes	365	20	0.81 (0.48-1.38)	0.90 (0.57-1.42)	230	15	0.93 (0.55-1.58)
Metabolic syndrome h
No	5,125	404	1	1	4,147	311	1
Yes	1,149	55	0.83 (0.59-1.15)	0.76 (0.56-1.01)	718	43	0.85 (0.61-1.18)
Number of metabolic syndrome h components
0	863	79	1	1	802	63	1
1	2,379	190	1.01 (0.74-1.36)	0.90 (0.69-1.19)	1,915	153	0.98 (0.72-1.33)
2	1,883	135	0.84 (0.59-1.19)	0.83 (0.61-1.13)	1,430	95	0.82 (0.58-1.16)
3	886	48	0.81 (0.52-1.27)	0.72 (0.49-1.07)	575	37	0.81 (0.52-1.27)
4	243	7	0.63 (0.26-1.48)	0.47 (0.21-1.05)	129	6	0.63 (0.27-1.49)
5	20	0			14	0
Number of metabolic syndrome h components
Increment by one component			0.90 (0.79-1.01)	0.88 (0.79-0.98)			0.90 (0.79-1.01)

OA = osteoarthritis; N = number of participants in respective category; n = number of disease cases in respective category; HR = hazard ratio; CI = confidence interval; BMI = body mass index; HDL = high-density lipoprotein.

^aAdjusted for age, gender, and BMI.

^bAdjusted for age, gender, BMI, history of physical workload, smoking history, difficulty walking due to disorder or complaint in the knees, and previous knee injury. For individual metabolic syndrome components: plasma fasting glucose, serum triglycerides, serum HDL, mean blood pressure, and central obesity, analysis was adjusted for other metabolic syndrome components. For combined variables: metabolic syndrome and number of metabolic syndrome components, no adjustment for individual metabolic syndrome components were performed.

^cSubscapular to triceps skinfold ratio >1.23.

^dSystolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive medication.

^eConcentration ≥5.6 mmol/L or diagnosed type 2 diabetes without insulin therapy.

^fConcentration ≥1.7 mmol/L.

^gConcentration <1.3 mmol/L in women and <1.0 mmol/L in men.

^hDefined as presence of any 3 or more of following 5 components: systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive drug treatment, serum triglycerides ≥1.7 mmol/L, serum HDL cholesterol <1.3 mmol/L among women and <1.0 mmol/L among men, plasma fasting glucose ≥5.6 mmol/L, and subscapular to triceps skinfold ratio >1.23.

The number of metabolic syndrome components at baseline was inversely associated with the risk of incident knee OA. In the full model, HR per increment by one component was 0.88 (95% CI [0.79, 0.98]) and the P value for the linear trend was 0.02 ( Table 3 ).

Of the individual metabolic syndrome components, none were associated with a significantly increased risk of incident knee OA. Elevated plasma fasting glucose level at baseline predicted significantly lower incidence of knee OA both when adjusted for age, gender, and BMI, and when adjusted for all the covariates (HR 0.71, 95% CI [0.55, 0.91]). After excluding the first 15 years of follow-up, risk reduction persisted as significant ( Table 3 ).

We observed some statistically significant interactions between metabolic syndrome, its components, and the covariates. Among women, central obesity predicted a significantly lower risk of incident knee OA (HR 0.53, 95% CI [0.30, 0.94], P = 0.016) but this was not the case among men (HR 1.17, 95% CI [0.86, 1.59], P value for interaction, 0.016). Among those with BMI in the range of 25.0 to 29.9 kg/m², elevated serum triglycerides showed a significantly lower risk of incident knee OA, unlike among those with higher or lower BMI (BMI < 25.0 kg/m²: HR 1.32, 95% CI [0.81, 2.15]; BMI 25.0-29.9 kg/m²: HR 0.55, 95% CI [0.38, 0.79]; BMI > 30.0 kg/m²: HR 1.20, 95% CI [0.78, 1.86], P value for interaction, 0.004). Knee complaints at baseline significantly modified the associations of metabolic syndrome, elevated mean blood pressure, and elevated triglycerides with the risk of developing knee OA ( Table 4 ). These factors predicted significantly reduced risks among the participants with knee complaints only.

Table 4.

Hazard Ratios with 95% Confidence Intervals for Incident Knee OA According to Certain Covariates among Those with and without Knee Complaints ^a at Baseline.

	No Knee Complaints a			Knee Complaints a			P Value for Interaction b
	N	n	HR (95% CI)	N	n	HR (95% CI)
Metabolic syndrome c	1,035	51	0.86 (0.63-1.18)	114	4	0.28 (0.10-0.80)	0.031
Elevated serum triglycerides d	1,546	91	0.97 (0.76-1.25)	174	9	0.39 (0.18-0.83)	0.023
Elevated mean blood pressure e	4,551	311	1.09 (0.85-1.40)	427	43	0.59 (0.31-1.12)	0.039

OA = osteoarthritis; N = number of participants in respective category; n = number of incident knee OA cases in respective category; HR = hazard ratio; CI = confidence interval.

^aSelf-reported difficulty walking or limping due to discomfort or trouble in knee during preceding month.

^bTested using likelihood ratio statistics.

^cDefined as presence of any 3 or more of following 5 components: systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive medication, serum triglycerides ≥1.7 mmol/L, serum HDL cholesterol <1.3 mmol/L in women and <1.0 mmol/L in men, and plasma fasting glucose ≥5.6 mmol/L, and subscapular to triceps skinfold ratio >1.23.

^dConcentration ≥1.7 mmol/L.

^eSystolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive medication.

Discussion

In our prospective cohort study, the presence of metabolic syndrome at baseline did not predict incident knee OA leading to hospitalization. On the contrary, even after adjustment for a comprehensive set of potential confounding factors, the number of metabolic syndrome components and fasting plasma glucose concentration were inversely proportional to the risk of developing knee OA.

The current study found no significant association between having metabolic syndrome and the risk of incident clinical knee OA. The results of most previous studies^11,13-16,21 are in line with our results, although in one study ²⁰ the accumulation of metabolic syndrome components predicted the risk of total knee replacement due to knee OA even when adjusted for BMI. A recent systematic review ³¹ also concluded that current data suggest that metabolic syndrome is not associated with knee OA, which is in line with our results.

Central obesity is strongly associated with BMI, a known risk factor for knee OA.^32,33 In several previous studies,^{12-15,20,21,34-36} central obesity has predicted an increased risk of knee OA or total knee replacement due to OA in adjusted analyses, but in most of these studies, this association attenuated after adjustment for BMI. In 2 of these studies, the association of waist circumference and knee OA persisted after adjustment for BMI.^11,20 In a recent study, increased waist circumference was associated with a higher risk of total knee replacement due to OA among those aged under 70 years but not among those aged 70 years or over. ¹⁶ Our study is in line with the majority of these studies, as the results suggest no significant association between central obesity and the risk of incident knee OA. A recent review ³⁷ discussed how systemic and local adipose tissue might play different roles in knee OA pathogenesis, but the mechanisms behind this and its relevance remain unclear.

Although cartilage is avascular, it has been suggested that vascular pathology might play a role in OA pathogenesis.^38,39 This may be due to changes in the microvasculature of the subchondral bone or other joint tissues rather than direct effects on cartilage. Even in early knee OA, subchondral bone marrow lesions have been detected, which has led to a suggestion that the site of OA onset might be the subchondral bone rather than the cartilage tissue itself. The potential association between hypertension, low serum HDL concentrations, and high serum triglyceride concentrations has been hypothesized as originating from vascular pathology.^38,39

Several previous studies have focused on the association of hypertension and the risk of knee OA, but the results are controversial,^11-20,40,41 and in some, hypertension has been related to an increased risk of knee OA.^{12,13,17-20,40} In some studies,^13,40 after adjustments for BMI this association has attenuated, but in others^12,17,19,20 it has persisted. In yet other studies, hypertension was not associated with an increased risk of knee OA or total knee arthroplasty, even without adjustment for BMI.^11,14,15 In one study, hypertension was related to the risk of bilateral radiographic knee OA independent of BMI, but was not related to unilateral knee OA. ⁴¹ A recent study found hypertension to be significantly associated with a risk of total knee replacement among participants aged under 50 years, but there was no significant association in older age groups. ¹⁶ A recent meta-analysis ⁴² showed an association between hypertension and knee OA. However, the findings of all studies, except for one, ¹⁹ which was included in the meta-analysis, were attenuated after adjustment for BMI. Therefore, confounding by BMI is possible, and these results may not indicate that hypertension is an independent risk factor for knee OA. The current study suggests that hypertension does not significantly increase the risk of incident clinical knee OA.

Our results suggest that elevated serum triglyceride concentrations do not predict incident knee OA. Serum hypertriglyceridemia was not associated with knee OA in the majority of previous studies.^11-16,41

A low level of serum HDL was not associated with knee OA in most studies,^{11,13-16,20,41} but in one Japanese study it was. ¹⁹ In another study, low HDL level was related to both radiographic and symptomatic knee OA among men, but not among women. ¹² The results of the current study suggest no correlation between low serum HDL and increased incidence of knee OA.

Our results do not suggest that elevated plasma fasting glucose levels or diagnosed diabetes without insulin therapy predict higher incidence of knee OA. Instead, our study observed that elevated plasma fasting glucose levels are related to a reduced risk of incident knee OA. Impaired fasting glycemia was associated with knee OA in some studies.^5,11,20 A recent systematic review found little evidence that impaired glucose metabolism was an independent risk factor for knee OA. ⁴³ Another recent review on the association between type 2 diabetes mellitus and OA discussed the effect of hyperglycemia on chondrocytes as being potentially mediating through oxidative stress and possibly even glucose toxicity during OA. ⁴⁴ However, another study found that supraphysiological glucose concentrations preserve glucose uptake, hyaluronan synthesis, and matrix integrity, and induce anti-inflammatory actions, thereby promoting cartilage repair in equine chondrocytes studied in vitro. ⁴⁵

As expected, female gender, higher BMI, heavy physical workload, previous knee injuries, and knee complaints predicted an increased incidence of knee OA, as reported previously.^7,30 In the current study, baseline knee complaints significantly modified the associations of metabolic syndrome, elevated mean blood pressure, and elevated serum triglycerides with the risk of developing knee OA: these factors predicted a reduced risk among those with knee complaints only. Possible explanations for this interaction are speculative. Knee complaints might, for example, lead to a reduced exercise rate and therefore affect the lipid profile and blood pressure levels, which is a possible explanation for the interaction. The finding suggesting that elevated serum triglycerides have a protective effect against developing knee OA among overweight individuals, but not among those with normal or below normal weight or obesity, does not seem rational at all. That central obesity among women, but not among men, is a predictor of lower knee OA risk, is plausible through different adiposity patterns and the possibly different predictive value of central obesity for knee OA among women compared with men. In all, the authors believe that the great number of interactions tested has led to significant findings by chance. The findings need therefore replication in further studies to confirm an interaction. It is also noteworthy that we had no a priori hypothesis on effect modification.

Smoking was associated with a reduced risk of incident knee OA. Some previous studies^8,12 as well as a meta-analysis ⁴⁶ observed that smoking had a protective effect on incident knee OA.

The current study had many strengths, but also some limitations. The main strengths of our study were its prospective design and the large, nationally representative and well-characterized population sample. The long follow-up period of 32 years was a major strength of this study. The reliability of knee OA diagnosis at baseline and the agreement between clinical and radiological diagnoses proved to be acceptable in quality estimations carried out as part of field examinations. ²⁵ Another strength of the study was its access to information on the major risk factors of knee OA at baseline. Although the detailed data on multiple knee OA risk factors allowed adjustment for potential confounders, the possibility of residual confounding cannot be ruled out.

One limitation of the current study was that the present data did not include information on waist circumference. Waist circumference and body fat distribution are better predictors of metabolic syndrome than BMI.^47,48 The available data on the subscapular to triceps skinfold ratio were used as a proxy for central obesity. There is, however, no clear limit as to what ratio threshold would correspond to the waist circumference threshold generally used ⁹ for central obesity. Among the Finnish adult population, the prevalence of central obesity, defined as waist circumference over 100 cm among men and 90 cm among women, was 23.2% (age standardized 22.4%) among men and 18.3% (age standardized 17.6%) among women in 1987. ²⁸ Therefore, we decided to use the highest quintile of subscapular to triceps skinfold ratio to approximate abdominal obesity. Another limitation of our study was that the follow-up covered knee OA cases admitted to hospital, but only a part of all patients suffering from knee OA are ever hospitalized. The hospitalized patients may not be representative of all the people who develop knee OA. The incidence of knee OA in this study was 6% among men and 9% among women. In the Health 2000 survey, conducted in a similar nationally representative study population, the prevalence of knee OA in the Finnish population aged over 30 years was 5% among men and 7% among women. ⁴ This supports the assumption that the amount of missed knee OA cases over follow-up is low. The criteria for hospitalization may also have changed over time. For example, the rate of arthroscopy procedures of osteoarthritic knees has declined. However, this may not have led to many missed cases in our study, as these patients still need specialist consultation in secondary health care, and would therefore mostly be recorded in the register. Furthermore, we cannot rule out that some early knee OA cases were missed by the physicians during the baseline examination. Some of the incident knee OA cases may also have been induced by a traumatic injury during follow-up. Furthermore, the participants’ way of life might have changed during the follow-up and this may have led to alterations in the covariates. The duration of fasting before blood sampling probably varied among the participants. This might have changed the estimates, but the direction of this change is conservative.

In conclusion, our findings do not support the hypothesis that metabolic syndrome or its individual components increase the risk of clinical knee OA. In fact, the number of metabolic syndrome components seemed inversely proportional to this risk. Whether elevated plasma fasting glucose levels predict a reduced risk of knee OA merits testing in further studies.