Osteoarthrosis Knee in the Elderly Risk Factors

ARTHRITIS & RHEUMATISM Vol. 40, No. 4, April 1997, pp 728-733 0 1997, American College of Rheumatology 728

RISK FACTORS FOR INCIDENT RADIOGRAPHIC KNEE OSTEOARTHRITIS IN THE ELDERLY

The Framingham Study

DAVID T. FELSON, YUQING ZHANG, MARIAN T. HANNAN, ALLAN NAIMARK, BARBARA WEISSMAN, PIRAN ALIABADI, and DANIEL LEVY

Objective. Knee osteoarthritis (OA) is highly prevalent, especially in the elderly. Preventive strategies require a knowledge of risk factors that precede disease onset. The present study was conducted to determine the longitudinal risk factors for knee OA in an elderly population.

Methods. A longitudinal study of knee OA involv- ing members of the Framingham Study cohort was performed. Weight-bearing knee radiographs were obtained in 1983-1985 (baseline) and again in 1992-1993. Incident disease was defined as the occurrence of new radiographic OA (Kellgren and Lawrence grade 2 2 on a 0-4 scale) in those without radiographic OA at baseline. Risk factors assessed at baseline and in the interim were tested in univariate and multivariate equations to evaluate their association with incident knee OA.

Results. Of 598 patients without knee OA at baseline (mean age 70.5 years, 63.7% women), 93 (15.6%) developed OA. After adjustment for multiple risk factors, women had a higher risk of OA than did men (adjusted odds ratio [OR] = 1.8, 95% confidence interval [95% CI] 1.1-3.1). Higher baseline body mass

Supported by NIH grants AG-09300 and AR-20613 and by an Arthritis Foundation New Investigator Award to Dr. Zhang.

David T. Felson, MD, MPH, Yuqing Zhang, DSc: Boston University Arthritis Center, Boston University Medical Center, and Boston City Hospitals, Boston, Massachusetts; Marian T. Hannan, DSc: Boston University Arthritis Center, Boston, Massachusetts; Barbara Weissman, MD, Piran Aliabadi, MD: Brigham and Womens Hospital, Boston, Massachusetts; Daniel Levy, MD: The Framingham Heart Study, Framingham, Massachusetts, and the National Heart, Lung, and Blood Institute, Bethesda, Maryland.

Dr. Naimark is deceased. Address reprint requests to David T. Felson, MD, MPH,

Boston University School of Medicine, 80 East Concord Street, Room A203, Boston, MA 02118.

Submitted for publication June 5, 1996; accepted in revised form October 14, 1996.

index increased the risk of OA (OR = 1.6 per 5-unit increase, 95% CI 1.2-2.2), and weight change was directly correlated with the risk of OA (OR = 1.4 per 10-lb change in weight, 95% CI 1.1-1.8). Physical activity increased the risk of OA (for those in the highest quartile, OR = 3.3, 95% CI 1.4-7.5). Smokers had a lower risk than did nonsmokers (for those who smoked an average of 1 1 0 cigarettedday, OR = 0.4, 95% CI 0.2-0.8). Factors not associated with the risk of OA included chondrocalcinosis and a history of hand OA. Weight-related factors affected the risk of OA only in women.

Conclusion. Elderly persons at high risk of developing radiographic knee OA included obese persons, nonsmokers, and those who were physically active. The direction of weight change correlated directly with the risk of developing OA.

Osteoarthritis (OA) is the most common joint disease, especially in the elderly. However, partly because of the slow time course of disease development, no substantial longitudinal studies of risk factors for the disease have been performed. Knowledge of the risk factors for knee OA has been derived from cross- sectional studies.

Similar to many chronic diseases, the pathogen- esis of OA is likely to be multifactorial. Risk factors consistently associated with the disease in cross-sectional studies include older age, female sex, and being over- weight (1). In cross-sectional studies, the OA could develop first, leading a person to become sedentary and to gain weight. We have reported that higher weight in early life predisposes patients to knee OA (2), and that weight loss lowers the risk of developing symptomatic knee OA (3). Both results were based on a one-time assessment of OA occurrence (3). We (4) and others ( 5 )

RISK FACTORS FOR KNEE OA 729

have also reported an association between nonsmoking and a high risk of OA, although this remains controver- sial and has not been evaluated in a longitudinal study. The relationship of physical activity and knee injury to OA risk has not been studied longitudinally. Physical activity could affect the risk of OA, but, because of OA-related reductions in activity, this association cannot be validly assessed cross-sectionally.

The reported association of chondrocalcinosis, or radiographic cartilage calcification, with OA in cross- sectional studies (6,7) may be due to the deposition of calcium pyrophosphate dihydrate crystals in already degenerated cartilage. The relationship of chondrocalcinosis to the development of OA is unknown.

OA is difficult to evaluate because it is a disease that combines both symptoms and pathologic changes, the latter of which are usually visualized by radiography. The standard for epidemiologic studies has been radiographic evaluation, which is a proxy for disease pathol- ogy. Recent studies using expensive imaging techniques such as arthrography, arthroscopy, and magnetic reso- nance imaging have documented that, when radiographic changes are present, these changes can also be detected using other techniques (8-11).

To evaluate the risk factors associated with the development of radiographic knee OA, we studied a population-based group of elderly patients in Framing- ham, Massachusetts. We assessed risk factors at the time of a baseline knee radiograph, and then reevaluated the patients for the development of radiographic OA -8 years later.

SUBJECTS AND METHODS

Subjects. The Framingham Heart Study was estab- lished in 1948 as a population-based study to evaluate risk factors for cardiovascular disease. Cohort members have since been examined every 2 years. A substudy, the Framingham OA Study, was begun at biennial examination 18 (1983-1985) to evaluate the prevalence of knee OA and associated risk factors in a population-based sample of elderly persons. The substudy population was similar in age, knee symptoms, and sex distribution to the underlying Framingham cohort (12). The OA examination included an anteroposterior (AP) weight-bearing knee radiograph and questions about knee symptoms and previous knee injury.

In 1992-1993, as part of Framingham biennial examination 22, the OA assessment was repeated using the same methodology, including AP weight-bearing radiographs (13). The followup study included radiographs obtained at home, or in a nursing home for those too frail to come to the clinic site. The longitudinal films were read by 2 different sets of readers. The reading protocol, including observer agreement and the team strategy, which was adopted to improve the accuracy and

precision of the readings, is described elsewhere (13). When the readers disagreed on whether patients had experienced incident disease, an adjudication session was carried out to reach a consensus. Radiographs were read according to a modified Kellgren and Lawrence scale (14), which character- izes knees as having OA (grade 2 2 on a 0-4 scale) if definite osteophytes are present.

A subject was defined as having incident radiographic knee OA if, at the baseline examination, both knees had grade

730 FELSON ET AL

patients for whom we obtained this measurement at examination 20 did not affect the results presented herein.

Statistical analysis. To examine the relationship between each risk factor and the occurrence of incident OA, we first calculated the cumulative incidence rate over the study period according to categories of each risk factor. A crude odds ratio (OR) was then obtained using, as a reference group, the risk of disease among subjects who did not have each factor. To obtain a multivariate-adjusted OR for each risk factor, a logistic regression model was used, with incident disease in each knee (not in each person) as the dependent variable. The standard error for each OR was adjusted for the correlation between knees (17), according to the approach described by Liang and Zeger (18). This method provides more efficient and valid point estimates than either knee- specific analyses or person-specific analyses (17).

The dependent variable in these analyses was the presence or absence of incident disease. An adjusted OR was computed, with approximate 95% confidence intervals (95% CI), based on maximum likelihood-derived standard errors.

RESULTS

In the original Framingham Knee OA Study, there were 979 subjects, among 1,437 studied, whose radiographs at baseline showed no evidence of knee OA. Of these subjects, 256 died prior to the followup study and 125 who remained alive did not participate. Among the 598 subjects for whom we obtained radiographs at followup (82% of survivors), 217 were men and 381 were women. Compared with participants in the followup examination, the nonparticipants tended to be older, were more often male, were more likely to smoke at least 10 cigarettes a day, and were somewhat more sedentary (Table 1).

The relationship of each risk factor to the development of incident knee OA is presented in Table 2. Age had no effect on the risk of incident disease among this elderly population (mean age 70.5 years, range 63-92). Women were at higher risk than were men, an association which persisted after adjustment for other risk factors.

High BMI at the baseline examination was strongly associated with an increased risk of incident OA. Analyses using weight at the baseline examination showed similar results. Weight change correlated directly with risk, with a 40% increase in risk per 10-lb weight gain and a commensurate decrease in risk for weight loss (P = 0.02 for weight change as a continuous measure). In the separate adjusted analyses, subjects were divided into 3 groups: those gaining 5 lb or more, those losing at least 5 Ib, and all others. We found that those with weight gain had an increased risk of OA (OR = 3.8, 95% CI 0.7-20.7) and those with weight loss

Table 1. Characteristics of participants and nonparticipants in the current study who had no knee osteoarthritis (OA) at the baseline examination in the Framingham Knee OA Study*

Nonparticipants

Participants Dead Alive Variable (n = 598) (n = 256) (n = 125)

Mean t SD age, years 70.5 -C 4.9 75.0 2 6.6 72.0 ? 4.9 Sex, no. (%) female 381 (63.7) 108 (42.2) 73 (58.4) Mean 2 SD BMI, 25.9 ? 3.9 25.4 2 4.2 25.2 f 3.7

Mean i SD weight -1.0 t- 10.1 -5.2 2 10.1 -1.2 t- 10.7 kgim'

change, lb (n = 93) (n = 76) Cigarette smoking at

examinations 1-18, no. (%)

Nonsmoker 266 (44.5) 100 (39.1) 44 (35.2) 1-9 cigarettes1day 181 (30.3) 70 (27.3) 39 (31.2) 210 cigarettesiday 151 (25.3) 86 (33.6) 42 (33.6)

examination 18, no. (%)

no. (%)

no. (%)

examination 10, no. (%)

Activity Index?

Knee injury before 191582 (3.3) 151251 (6.0) 131122 (2.5)

Interim knee injury, 16 (2.7) NA NA

Chondrocalcinosis, 441581 (7.8) 33/256 (12.9) 71123 (5.7)

Hand OA at 1261393 (32.1) NA NA

Mean 2 SD Physical 33.5 ? 5.3 32.1 ? 5.8 32.5 ? 4.8

* BMI = body mass index; NA = not available. t This index is a weighted summary of activity based on kilocalories of energy expended during a typical day.

had a lower risk of O A (OR = 0.5, 95% CI 0.2-1.1). While BMI at the baseline examination (1983-1985) affected OA risk, BMI earlier in life (at biennial examination 1 [1948-19511) had a more modest and nonsig- nificant effect on OA risk (per 5 units of BMI, OR = 1.5,

The mean number of cigarettes smoked per day between examinations 1 and 18 was inversely associated with the risk of disease (P < 0.001 for trend) (Table 2). Furthermore, only 16 subjects experienced major knee injury in the 8 years between the baseline and followup examinations. There was a slight increase in their risk of developing incident knee OA, although the point estimates were imprecise. Knee injury prior to the baseline examination did not affect the risk of incident OA

Presence of chondrocalcinosis at the baseline examination had little effect on the development of knee OA. The presence of hand OA -15 years prior to the baseline examination also did not affect the risk of OA

Habitual physical activity increased the risk of

95% CI 0.95-2.4).

(OR = 0.7, 95% CI 0.1-3.2).

(OR = 0.9, 95% CI 0.5-1.8).

RISK FACTORS FOR KNEE OA 73 1

Table 2. (OA) among the elderly cohort*

Relationship of risk factors to incident knee osteoarthritis

Cumulative incidence of Crude Adjusted

Risk factors OA, no. (%) OR OR (95% CI)t

Age per 5-year difference

Sex Male Female

BMI per 5-unit difference

Weight change per 10-lb difference

Cigarette smoking at examinations 1-18

Nonsmoker 1-9 cigarettesiday 210 cigarettes/

Interim knee injury day

No Yes

No Yes

No Yes

Hand OA No Yes

Physical activity levels 1st quartile 2nd quartile 3rd quartile 4th quartile

Past knee injury

Chondrocalcinosis

-

241217 (11.1) 691381 (18.1)

-

-

541266 (20.3) 251181 (13.8) 141151 (9.3)

891582 (15.3) 4/16 (25.0)

911579 (15.7) 2/19 (10.5)

831537 (15.5) 8/44 (18.2)

381267 (14.2) 171126 (13.5)

141134 (10.4) 201134 (14.9) 261132 (19.7) 231131 (17.6)

1.1

1.0 1.8 1.6

1.4

1.0 0.6 0.4

1.0 1.8

1 .o 0.6

1.0 1.2

1.0 0.9

1.0 1.5 2.1 1.8

1.2 (0.9-1.5)

1.0 1.8 (1.1-3.1) 1.6 (1.2-2.2)

1.4 (1.1-1.8)

1 .o 0.7 (0.4-1.2) 0.4 (0.2-0.8)$

1.0 1.6 (0.4-5.7)

1.0 0.7 (0.1-3.2)

1.0 1.2 (0.5-2.7)

1.0 0.9 (0.5-1.8)

1.0 2.4 (1.0-5.3) 3.1 (1.4-6.9) 3.3 (1.4-7.5)$

- * OR = odds ratio; 95% CI = 95% confidence interval; BMI = body mass index. t Adjusted simultaneously for all other risk factors listed. $ P < 0.001, test for trend. 0 Quartiles are sex-specific and range from sedentary (1st) to high activity levels (4th).

knee OA. Patients in the highest quartile of physical activity at the baseline examination had 3.3 times the odds of developing OA (95% CI 1.4-7.5) compared with those in the lowest quartile of physical activity, the most sedentary group. For each increase in level of physical activity, there was a higher risk of knee OA (P < 0.001 for trend). We found no association between OA risk and physical activity at examinations 4 and 12 (e.g., compared with those in the lowest quartile, those in the highest quartile of physical activity had a risk of developing OA in later life of 1.2 [P = 0.551). Sixty-seven subjects did not receive an assessment of physical activity at examination 20 (most did not attend examination 20), but were assessed at earlier examinations. When

comparing these subjects with subjects who provided information on physical activity at examination 20, nei- ther their earlier physical activity levels (33.1 versus 33.6; P not significant [NS]) nor their rates of OA incidence (14.9% versus 15.6%; P NS) differed significantly.

To assess whether the effect of each risk factor on incident knee OA varied according to sex, we stratified study subjects according to sex (Table 3). For women, higher levels of adiposity were strongly and significantly associated with an increased risk of knee OA incidence (for each 5-unit increase in BMI, OR = 1.8, 95% CI 1.2-2.6). Furthermore, the effect of weight change was seen only in women (for each 10-lb weight change, OR = 1.6, 95% CI 1.2-2.3; P = 0.008 for weight change as a continuous variable). For men, we were limited by the small number of incident cases (n = 24). Increases in the BMI in men did not translate into an increased OA risk (OR = l.O), nor did weight change have a significant effect in men. Other risk factors differed, but wide confidence intervals limited the interpretability of the results.

Physical activity was assessed at examination 20, midway between the baseline and followup examinations. Because symptoms could conceivably affect physical activity level, we divided subjects into those with knee symptoms at either baseline or followup versus those with no knee symptoms (Table 4). Although high levels of physical activity translated into extremely high risks of incident disease in the 53 patients with knee symptoms (OR = 57.4), these estimates were very imprecise. Importantly, among those with no knee pain,

Table 3. Relationship of risk factors to incident knee OA by sex*

Adjusted OR (95% CI)t

Risk factor

Age per 5-year difference BMI per 5-unit difference Weight change per 10-lb difference Cigarette smoking at examinations

1-18 Nonsmoker 1-9 cigarettesiday 210 cigarettedday

Interim knee injury Past knee injury Chondrocalcinosis Hand OA Physical activity level, 1st quartile vs.

4th auartilei

Male Female (n = 69) (n = 24)

0.9 (0.5-1.6) 1.3 (0.9-1.7)

0.9 (0.5-1.5) 1.6 (1.2-2.3) 1.0 (0.5-2.1) 1.8 (1.2-2.6)

1 .o 1.0 1.2 (0.5-3.3) 0.6 (0.3-1.1) 0.3 (0.1-1.2) 0.5 (0.2-1.2)

3.8 (0.3-48.1) 0.3 (0.03-2.4) 1.3 (0.3-6.9) 1.1 (0.4-3.0) 1.7 (0.5-6.0) 0.7 (0.3-1.7) 3.8 (0.9-17.3) 3.1 (1.1-8.6)

- 2.0 (0.5-7.4)

* See Table 2 for definitions. t Adjusted simultaneously for all risk factors, as listed in Table 2. $ Quartiles range from sedentary (1st) to high activity levels (4th).

732 FELSON ET AL

Table 4. thritis (OA) according to symptoms*

Relationship of physical activity to incident knee osteoar-

Adjusted OR for OA (95% CI)$

Knee symptoms Physical activity level present Knee symptoms

(n = 468)t (n = 53) absent

1st quartile 1.0 1.0 2nd quartile 13.7 (0.5-362.5) 1.9 (0.8-5.0) 3rd quartile 6.4 (0.1-320.1) 2.6 (1.0-6.4) 4th quartile 57.4 (1.6-2,107.3) 2.1 (0.8-5.5)

* Presence of knee symptoms was based on a positive response to the knee symptom question (13) at either baseline or the followup examination. Information on symptoms was missing for 63 patients (48 non-OA, 15 OA). OR = odds ratio. 95% CI = 95% confidence interval. t Quartiles range from sedentary (1st) to high activity levels (4th). $ Adjusted simultaneously for all risk factors, as listed in Table 2. P < 0.01, test for trend, in those with knee symptoms; P = 0.04, test for trend, in those without knee symptoms.

increased physical activity was similarly associated with elevated risks of OA development.

To further explore the association of smoking with incident disease, we looked at smoking status at the baseline examination. Current smokers (n = 70) also had a somewhat lower risk of incident knee OA than did nonsmokers (adjusted OR = 0.7, 95% CI 0.3-1.6). Former smokers at examination 18 had a lower-than- expected risk of incident OA (adjusted OR = 0.5, 95% CI 0.3-0.9).

DISCUSSION

This study of radiographic OA suggests that the following risk factors increase the risk of incident OA: female sex, obesity, nonsmoking, and high levels of physical activity. For adiposity, smoking, and physical activity, there was a gradient of risk, whereby higher levels of exposure affected disease risk more than lower levels. Our study was performed among subjects who were elderly at baseline.

This is the first large-scale incidence study that evaluates persons without baseline knee OA. A prior population-based study was performed (19), but was, unfortunately, based on a small number of OA cases (13 cases in 123 men followed up and 36 cases in 135 women). Except for an effect of BMI on OA risk in women, tested risk factors showed no consistent or significant effect on disease incidence.

Many cross-sectional studies, including a previous one from the Framingham OA Study, have consistently documented the strong association of adiposity

with OA. Our study proves that adiposity precedes OA development, extending previous results, and also suggests a sex difference in the relationship between adiposity and OA. A sex difference has also been seen in some (2,19-21), but not all (22), prior studies. Although our earlier cross-sectional study using a one-time OA assessment suggested that weight loss protected against the development of symptomatic OA (3), this is the first study to document an effect of weight change on the development of OA. Why obesity causes knee OA is not entirely clear, although increased joint loading probably plays a role. The link between obesity and hand OA (23) and the high risk of OA only among women with a high BMI suggest that increased joint stress in obese patients may not be the sole explanation.

We did not find an association between increased age and the development of OA, but our sample was elderly at study inception. Other studies of incident disease (24) have reported that both women and men face increased risks of disease as they get older, but that disease incidence may plateau when persons reach their 70s, the mean age of our population.

The effect of physical activity on disease occurrence is of interest. Recent studies of runners (25-28) reported that those who were highly physically active may face an increased risk of radiographic OA. Several small longitudinal studies (29,30) have shown no increased OA risk in runners. Our study, in combination with most others, suggests that physical activity predisposes to structural changes related to OA. The population we studied was elderly, and many of those in the referent group were extraordinarily sedentary. High levels of physical activity in these age groups may fall into the normal range in younger persons.

While joint injury likely causes knee OA, too few of our subjects experienced knee injuries for us to evaluate this definitively as a risk factor for OA. Those with past knee injury probably had developed knee OA by baseline and were, therefore, not eligible for this study. Our null finding regarding chondrocalcinosis is also limited by imprecision. Our results suggest that the presence of chondrocalcinosis, a frequent finding in the elderly that reflects crystal deposition, is not associated with a high risk of OA development.

Smoking appears to decrease the risk of developing OA. In cross-sectional studies, others (4,5,20,31) have also reported that subjects with OA are less likely to be smokers than are their matched controls. However, this finding is not universal (32). While smokers tend to be thinner than nonsmokers, adjustments for weight and change in weight did not affect this negative association.

RISK FACTORS FOR KNEE OA 733

Smoking is known to favorably affect rates of other diseases such as inflammatory bowel disease, and it is conceivable that one of the many constituents of smoke could act to prevent cartilage destruction. We suspect that former smokers had a lower risk of OA than nonsmokers because smoking may delay the gradual development of cartilage loss and joint degeneration.

In this first large-scale incidence study of knee OA, we found that female sex, adiposity, and nonsmoking increased the risk of developing disease. Further- more, elderly persons with high physical activity levels had a high rate of incident radiographic OA, and weight change also correlated directly with OA risk.

ACKNOWLEDGMENTS

We are indebted to Nilsa Carrasquillo for her technical assistance, to Diane Weiland and Bryan Besso for obtaining the knee radiographs, to Dr. Tim McAlindon for his helpful suggestions, and to the Framingham Study patients for their participation.

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Osteoarthrosis Knee in the Elderly Risk Factors

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