Osteoarthritis protects against femoral neck fracture: The MEDOS study experience

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Bone, 14. S5 I -S56, ( 1993) Printed in Great Britain. All rights reserved.

Osteoarthritis Protects Against Femoral Neck Fracture: The MEDOS Study Experience J. DEQUEKER,’

0. JOHNELL2

and THE MEDOS STUDY

GROUP3

‘Arthritis and Metabolic Bone Disease Research Unit, K. U. Leuven. Belgium ‘Department of Orthopaedics, Malmir General Hospital, Sweden ‘Collaborating Centres: Dilsen. G., Istanbul; Gennari. C., Siena; A. A. Lopes Vaz. Porto; G. Lyritis, Athens; G. D. Mazzuoli. Rome; L. Miravet. Paris; M. Passeri, Parma; R. Pt%ez-Cane, Seville; A. Rapado, Madrid; C. Ribot, Toulouse Project Group: E. Allander, WHO Collaborating Centre for the Epidemiology of Rheumatic Conditions, Hudding; J. Dequeker, WHO Consultant, Leuven: A. Gonzalez, Sandoz Base/; J. A. Kanis, European Osteoporosis Foundation, Shefield; D. Loew, Sandoz Basel; N. Khaltaev, WHO Non-Communicable Diseases, Geneva: M. Pluss. Sandoz Base1 Address for correspondence and reprints: Professor Dr. J. Dequeker, Arthritis and Metabolic Bone Disease Research Unit, KU Leuven, UZ Pellenberg, B-3212 Pellenberg, Belgium.

Abstract The relationship betweeu osteoarthritis and osteoporosis (hip fracture) was studied using the data from the MEDOS study, a large prospective epidemiological study of femoral neck fracture patients and age-matched controls in the Mediterranean area. Osteoarthritis was found to be protective against hip fracture in both men and women, with a significant reduction of the relative risk factor for osteoporosis (relative risk = 0.48 and 0.68, respectively, p < 0.001). The age-adjusted relative risk factor for osteoporosis remains even after adjustment for body mass index, indicating that body mass index and osteoarthritis are independent relative risk factors for hip fracture. The mean age of the group with co-existent osteoarthritis and hip fracture was significantly higher for both men and women, compared to the group with osteoporosis alone. This indicates that if osteoarthritic subjects develop osteoporotic fracture, they do so at a lPter age. The osteoarthritic cases compared to controls and hip fracture cases were significantly smaller in stature in both sexes, and women had a significantly higher body weight and body mass index. Extra-capsular hip fracture was significantly more frequent in cases with concomitant osteoarthritis. These findings confirm earlier observations that osteoarthritis and osteoporosis are two distinct diseases and not phenomena related solely to ageing. Key Words: Osteoporosi.s-Osteoarthritis-Body -Hip fracture-Age--Sex.

mass index

Introduction Osteoporosis and osteoarthritis are two common age-related musculoskeletal disorders associated with considerable morbidity and mortality. Patients with post-menopausal osteoporosis (OP) and those with osteoarthritis (OA) appear to represent anthropometrically different populations (Dequeker et al. 1983). General clinical experience is that, although both common in elderly patients, osteoporosis and osteoarthritis (Urist 1960; de Seze et al. 1962; Foss & Byers 1972; Roh et al. 1974; Christiansen et al. 198 1; Cooper et al. 199 I; VerstraeS51

ten et al. 199 1), and, in particular, fractures and osteoarthritis of the hip, seldom occur together (Pogrund et al. 1982; AstriSm & Beertema 1992), and that osteoarthritis of the hip is a negative risk factor for compression fractures of the spine (Healey et al. 1985). Clinical studies investigating the negative association between osteoarthritis and osteoporosis may be limited by selection bias in the ascertainment of cases of both osteoporosis and osteoarthritis. A large prospective epidemiological study of femoral neck fracture patients and age-matched controls could provide an unbiased means of testing the hypothesis that there is an inverse relationship between osteoporosis (hip fracture) and osteoarthritis. The MEDOS project is such an epidemiological study, and the purpose of this investigation was to report the results concerning the relationship between osteoarthritis and hip fracture as observed in the MEDOS study. Patients and Methods The MEDOS study is a prospective study of the incidence of, and risk factors for, hip fractures in countries along the northem rim of the Mediterranean, involving 14 centres from six countries. The MEDOS questionnaire (Dequeker et al. 1991) was applied prospectively to 2,8 16 patients (aged more than 50 years) admitted to the hospital, and to 5,369 sex-matched controls over a period of 1 year (1988-1989). The controls were: sampled from population registers; neighbours to cases; sampled from persons having fallen but not experienced hip fracture; or sampled from hospital controls. Of the 9 15 variables of the questionnaire, one question in the section “diseases of the musculoskeletal system” (Section 7.7.1.) deals with osteoarthritis, asking the patient if he or she was told that he or she suffered from osteoarthritis (no, yes, definite or probable). A reliability study was performed including both cases and controls. Two hundred and twenty-eight patients or controls were re-interviewed by a different interviewer after a median time of 7 days. The test used for concordance was Kendall’s Tau B, which showed 91.6% concordance for osteoarthritis and 85.3% Kendall’s Tau B.

s52

J. Dequeker et al.: Osteoarthritis and osteoporosis: The MEDOS experience

Table 1. Patient characteristics-women Control patients -Osteoarthritis n

Age (years) Height (cm) Weight (kg) BMI

Hip fracture cases +Osteoarthritis

1,658 77.2 * 9.3 159.0 + 6.9 60.0 + 11.2 24.5 f 4.2

2,299 77.5 * 8.0 157.8 + 6.7b 61.4 ? I 1.5b 25.5 + 4.8b

-Osteoarthritis

+Osteoarthritis

1,041 77.6 f 9.5 158.7 + 7.3’ 57.1 f 11.0’ 23.2 f 4.5’

1,029 78.5 f 8.7’ 158.8 + 6.3 58.9 + 12.1b 24.0 k 4.9b

’ p < 0.05, “p < 0.001: vs. - Osteoarthritis group. ‘p < 0.00 I: vs. + Osteoarthritis controls.

Statistical methods Student’s

t-test, the Chi-squared

test, and a logistic regression

model controlling for age were used when appropriate. Results

The cases and controls were divided into four groups: a) controls without osteoarthritis; b) controls with osteoarthritis; c) hip fracture without osteoarthritis; and d) concomitant hip fracture and osteoarthritis. Characteristics of the osteoarthritis cases, controls, hip fracture cases, and cases with co-existence of hip fracture and osteoarthritis are compared in Table I (women) and Table II (men). Osteoarthritis cases of both sexes had a significantly smaller body height than controls, and in women the mean body mass index (BMI: weight/ height, a measure of obesity), was also significantly higher. In both sexes, hip fracture cases were significantly taller, and had significantly lower body weight and BMI, than controls with osteoarthritis. In men, the mean age of the group with co-existent hip fracture and osteoarthritis was significantly higher than that of the group with hip fracture alone. Figures 1 and 2 show the mean body height, body weight, and BMI for each study centre separately (Fig. 1: women; Fig. 2: men). The results were comparable with the overall characteristics for almost all centres. The age-adjusted relative risks posed by osteoarthritis for hip fracture are shown for both sexes in Table III. Osteoarthritis was found to be a strong negative risk factor for hip fracture. The overall relative risk factor for definite osteoarthritis was 0.64 (p < 0.00 1). For men, the relative risk was 0.48 (p < O.OOl), and for women it was 0.68 (p -z 0.001). When probable osteoarthritis was included, the negative relative risk remained highly significant. The age-adjusted negative relative risk for hip fracture in

osteoarthritis cases was also observed in the individual centres. The lowest values were observed in rural Turkey, Istanbul and Seville (Table IV). The prevalence of definite or probable osteoarthritis (as reported by the questionnaire) varied widely between centres and even within one country (Table V). The overall prevalence was 58% in women and 38% in men, with a female/ male ratio of 1.5 1. In three centres (Paris, Crete, and rural Turkey) the prevalence was particularly low, without affecting the female/male ratio. The prevalence of osteoarthritis in the hip fracture cases also varied between centres, in the same way as the prevalence in the controls. Osteoarthritis was present in 49% of women and 26% of men with hip fracture. Extra-capsular hip fracture was significantly more frequent in women with concomitant osteoarthritis than in those without, 63% versus 52% (p < O.OOl), as shown in Table VI. Discussion

We found a strong and constant negative association between osteoarthritis and hip fracture. This negative association was more pronounced for men than for women. The age-adjusted relative risk factor of 0.68 remained at 0.74 even after adjustment for BMI, indicating that BMI and osteoarthritis are independent relative risk factors for hip fracture. We found that osteoarthritis cases of both sexes were significantly smaller in stature than controls and hip fracture cases, and that in women, osteoarthritis cases also had higher body weight and BMI. Finally, we found that the cases with co-existent hip fracture and osteoarthritis were significantly older than the other groups. The definition of osteoarthritis cases used in this study was based on results from a questionnaire and, thus, was

Table Il. Patient characteristics-men Control patients -Osteoarthritis n

Age (years) Height (cm) Weight (kg) BMI ’ /I b ,I

< <

841 72.6 + 10.4 169.7 f 7.4 70.8 ?I I 1.7 25.1 f 4.2

Hip fracture cases +Osteoarthritis 526 75.1 + 9.6” 168.3 f 6.8’ 69.0 ? 1I .4’ 24.9 f 3.8

0.00 I : vs. - Osteoarthritis group. 0.00 I, ‘jr < 0.0 I. */I < 0.05: vs. + Osteoarthritis controls.

-Osteoarthritis 533 72.7 -t 10.7b 169.9 + 8.1b 67.0 f I 1.5’ 23.9 + 4.0b

+Osteoarthritis 188 76.9 f 8.7@ 168.6 f 8.7 68.7 f 8.9 24.4 + 3.6

H E b H T

W : G H T

B M I

Comparison of anthropomorphic characteristics Osteoarthritis (Def+Prob) - Hip fractures WOMEN MEDOS 92 Fig. 1. Patient characteristics in each MEDOS study

H

centre,

0

OA

m

Hip fracture

women.

190

E I G

170

H T

160

W E

90

T

70

‘G H T

B M I

50 I

30

20

Comparison of anthropomorphic characteristics Osteoarthritis (Def+Prob) - Hip fractures WOMEN MEDOS 92 Fig. 2. Patient characteristics in each MEDOS study centre, men. s53

0

OA

tzzl

op

s54

J. Dequeker et al.: Osteoarthritis and osteoporosis: The MEDOS experience

Table 111. Relative risk factors (RR), adjusted for age, in osteoarthritis cases Probable and definite osteoarthritis

JrR

Definite osteoarthritis

All

Women

Men

All

Women

Men

8,115 0.68’

6,022 0.71”

2,088 0.55”

7,539 0.64’

5,584 0.68’

1950 0.48’

without objective proof. This might weaken the importance of the above findings. However, the value of our findings is

strengthened by: the consistency of the anthropometric findings (body weight, height, and BMI) and the relative risk factors in all the different centres; the significant result of the reliability test for the question on osteoarthritis; and the fact that the doctors carrying out the interviews had medical knowledge of osteoarthritis. The difference in prevalence between centres and in particular the low prevalence of osteoarthritis in Paris, Crete, and rural Turkey could be explained by a more stringent interpretation of the definition of osteoarthritis on the part of the interviewers in these centres. In these three centres, doctors training in rheumatology and orthopaedics were used, and they looked for some evidence at the hands and knees also. Alternatively, genetic and environmental factors could also contribute to the differences between centres. This retrospective population study confirms previous observations that osteoarthritis is protective against osteoporosis, in particular, hip fracture (Urist 1960; Foss & Byers 1972; Roh et al. 1974; Christiansen et al. 1981; Pogrund et al. 1982; Weintroub et al. 1982; Dequeker et al. 1983; Healey et al. 1985; Felson et al. 1988; Cooper et al. 199 1; Verstraeten et al. 199 1; Astrijm et al. 1992). The BMI findings in this study are in line with those of previous reports that showed a significantly higher BMI in osteoarthritic cases compared to controls (Urist 1960; Foss & Byers 1972; Roh et al. 1973; Roh et al. 1974; Dequeker et al. 1983; Felson et al. 1988; van Saase et al. 1988; Davis et al. 1990; Bagge et al. 199 1; Geusens et al. 199 1; Verstraeten et al. 1991) and a significantly lower BMI in osteoporosis cases compared to controls (Pruznansky et al. 1989). The finding in this study of a significantly lower body height in osteoarthritis does not confirm our earlier studies in

clinical cases of osteoarthritis (Dequeker et al. 1983). This may be due to regional or genetic differences between Central Europe, Belgium, and Southern Europe, but may also be due to the fact that our earlier osteoporosis cases were vertebral collapse cases, while in the Mediterranean study the osteoporosis cases were hip fracture cases. Increased body height in patients with osteoporosis has also been observed in other studies and might explain why the incidence of osteoporosis is, for example, higher in Northern Europe, particularly in Sweden, and in Rochester, MN, where a large number of people of Scandinavian descent live (Paganini-Hill et al. 198 1; Nevitt et al. 1992). That osteoarthritis protects against osteoporosis is also supported by the data found in the group with concomitant osteoarthritis and hip fracture. In this group, the mean age was significantly higher than in those with osteoporosis alone, in both sexes. This finding confirms our earlier study concerning the co-existence of vertebral fracture and osteoarthritis of the spine (Verstraeten et al. 199 I), where we also found a significantly higher mean age in the co-existence group than in the group with vertebral fracture alone. The observation that extra-capsular hip fracture occurred more frequently in the group with co-existent osteoarthritis and hip fracture confirms the observation of Dretakis & Christodoulou (1983) that, in cases with osteoarthrosis of the hip or knee, pertrochanteric fracture occurs preferentially. Despite strong data showing that osteoarthritis protects against, or retards the development of, osteoporosis, the biological explanation for this link is not yet clear. Osteoarthritis is usually considered as a disease of cartilage failure with secondary bone changes such as osteophytes and subchondral sclerosis. Osteoporosis, on the other hand, is considered to be an age-related condition character&d by a reduced amount of bone, leading to diminished physical strength of the skeleton and an increased susceptibility to fracture.

Table IV. Relative risk factors (RR) for hip fracture in osteoarthritis, in the different MEDOS study centers Women

Table V. Prevalence of definite and probable osteoarthritis MEMOS study, control population

Men

Centre

N

RR

N

RR

Paris Toulouse Crete Rome Siena Parma Port0 Madrid Seville Istanbul Rural Turkey Ankara

556 1,070 582 1,229 376 440 276 228 559 439 92 170

0.71 0.99 0.93 0.78’ 0.68 0.92 0.75 0.64 0.44b 0.42b 0.18’ 0.6 I

107 263 237 217 129 127 84 72 157 311 246 138

0.67 0.82 0.45’ 0.76 0.42’ 0.71 1.29 I .36 0.35’ 0.33b 0.17b 0.71

‘!,<0.05,~~<0.001,=~<0.01.

Centre

Women

Men

Paris Toulouse Crete Rome Siena Parma Port0 Madrid Seville Istanbul Rural Turkey Ankara Total

37.0 69.6 20.8 60.0 64.8 51.0 69.4 56.6 66.3 74.3 33.8 74.3 57.6

24.0 47.9 21.7 56.8 40.8 23.5 27.4 27.1 27.8 53.0 25.5 54.6 38.2

in the

Ratio, women/men

I .54 I .45 0.96 1.06 1.59 2.17 2.55 2.04 2.38 1.40 I .32 1.36 1.51

J. Dequeker et al.: Osteoarthritis and osteoporosis: The MEDDS experience Table VI. Co-existence of different types of hip fracture and

s55

Conclusion

osteoarthritis Intra-capsular N Age (yea@ Women Men

Women -Osteoarthritis +Osteoarthritis

Mean+SD

Extra-capsular N

Mean + SD

878 289

77.1 + 9.7 73.2 f 10.4

1,183 420

78.8 + 9.17’ 74.8 + 10.2b

N

w

N

%

494 378

47.9 37.2

537 639

52.1 62.8

The inverse relationship between osteoarthritis and osteoporosis is not only ofacademic interest in explainingpathophysiological mechanisms of both diseases; it is also of interest in clinical practice and in decision-making on preventive measures. General osteoarthritis usually becomes manifest around the age of the menopause, before major bone loss occurs. Therefore, osteoarthritis could be a good negative indicator for selecting patients at risk for osteoporosis. The anthropometric, biological, and biochemical differences between primary osteoarthritis and osteoporosis reflect that systemic and metabolic factors are involved in the pathophysiology of this disease and that these common, crippling diseases are not a simple consequence of ageing.

x2 = b Men -Osteoarthritis +Osteoarthritis

216 69

42.2 37.5

69 115

57.8 62.5 x2 = NS

=p < 0.001, “p < 0.05.

At present, evidence is accumulating that osteoarthritis might initially be a bone disease rather than a cartilage disease. Osteoarthritis cases have a better preserved bone mass (Foss & Byers 1972; Roln et al. 1974; Carlsson et al. 1979), even independently of body weight (Gotfriedsen et al. 1990; Vandermeersch et al. 1990). Studies on iliac crest bone have shown differences in bone mass, biomechanical characteristics, biochemical composition, and mineralisation profile according to the presence of osteoarthritis in the hands (Gevers & Dequeker 1987; Gevers et al. 1989a, b; Raymaekers et al. 1992). Osteoarthritic women had significantly more bone and the bone was significantly stiffer, had a higher compressive strength, higher osteocalcin content and a mineralisation profile shifting to higher densities. These results are important because they demonstrate that patients with osteoarthritis have changes in bone quality in bone areas apparently unaffected by the disease. Two qualitative differences have been demonstrated between osteoarthritic and non-osteoarthritic bone at the iliac crest: firstly, in the bone of osteoarthritic patients, the density profile is shifted to higher densities compared with young and agematched controls; and secondly, in osteoarthritis, osteoblasts continue to produce and1 lay down in the matrix osteocalcin, as in young non-osteoarthritic bone. These findings support the hypothesis that quantitative and qualitative differentEs in bone may explain the inverse relationship between osteoarthritis and osteoporosis. These quantitative and qualitative differences in bone may produce disease by increasing subchondral bone stiffness and by making subchondral bone less deformable to impact loads. This stiff bone transmits more force to overlying cartilage, making it more vulnerable. The higher body weight in the osteoarthritisgroup, in addition to increased force on cartilage and bone, may also affect the bone density by preserving a better postmenopausal oestrogen status due to peripheral conversion of androstenedione to oestrone in subcutaneous fat. In contrast, in women with hip fractures who have a very low BMl, bone fragility may be evident earlier because ofan earlier and more pronounced

oestrogen dleficiency.

The authors wish to thank Mrs. J. Cartois and Ms. S. Vander Elst for expert secretarial help and Mr. J. Nijs and Mr. J. Aerssens for statistical assistance. The study was sponsored by the European Foundation for Osteoporosis and Bone Disease and the World Health Organisation, and was made possible by the financial support of the Sandoz Company.

Acknowledgments:

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