Results

The mean age of the study participants was 66.1 years. Overall, 55 of 475 women were using HRT (table 1). Of these, 29 were taking oestrogen only preparations and 26 used oestrogen-gestagen combinations. The median duration of use was 5.4 years with an interquartile range from 2.3 to 8 years. One hundred and ninety four women had prevalent hip OA, and 281 women had prevalent knee OA. Radiographs of the contralateral joint were available for 91% of the women (9% refused additional radiographs of the contralateral joint), and a bilateral hip or knee joint OA was observed in the majority of these patients (88.2%). For 79% of the women, radiographs of the hands were available (missing values attributable to patients refusing additional hand radiographs) and 34.7% of these had a GOA.

Table 2 shows the distribution of potential confounding variables according to the use of HRT. Looking at the median age, HRT users were seven years younger than non-users of HRT. Women with oestrogen intake were less likely to have diabetes and more likely to be current smokers and having had a hysterectomy. There were no major differences between the groups regarding body mass index, age at menopause, gout and thiazide use.

In table 3 we present the number of participants and the prevalence of bilateral and GOA according to oestrogen intake, followed by the crude and adjusted odds ratios (OR) and their 95% confidence intervals (CI) for the association between HRT use and the different OA patterns. Odds ratios above one correspond to a higher prevalence of bilateral or GOA in HRT users compared with non-users.

Women using HRT had a slightly lower prevalence of bilateral OA (86.3%) than women not using HRT (88.7%). This was mainly attributable to confounding by age, however. After adjustment for age and the other covariates, there was a weak, statistically non-significant positive association between oestrogen use and bilateral OA (OR=1.21; 95% CI: 0.48, 3.03).

Users of HRT had a somewhat lower prevalence of GOA (27.5%) compared with non-users (35.7%) resulting in a crude odds ratio of 0.68 (95%CI:0.33, 1.42). Again, the crude odds ratio was strongly confounded by age. After adjustment for confounding, there was a weak, statistically non-significant positive association between HRT and GOA (OR=1.21; 95% CI: 0.53, 2.74).

Conducting the analysis according to the duration of current oestrogen use, we found no major differences in the prevalences of generalised or bilateral OA between women who used HRT five years or more, less than five years, and non-users (table 4), but the small numbers in the subgroups have to be taken into account. Looking at women with use of oestrogen mono-preparations and oestrogen-gestagen combinations separately, we found no significant differences between either of the two subgroups in comparison with non-users concerning both bilateral and GOA (data not shown).

Discussion

In contrast with previous studies reporting a protective effect of HRT on knee or hip OA, we observed no association between HRT use and either bilateral knee or hip OA or GOA in the Ulm Osteoarthritis Study.

Two recent cross sectional studies found an inverse association between HRT and prevalent hip4 or knee5 OA. In the Chingford Study5 45–64 year old women were examined, and current users of HRT (for more than one year) showed a lower prevalence of knee OA, which was defined by osteophytes, than non-users (OR=0.31; 95% CI: 0.11, 0.93). In the Study of Osteoporotic Fractures4 participants 65 years or older were included. An inverse association of HRT use with hip OA, which was defined on a radiographic summary score,17 was observed (OR=0.63; 95% CI: 0.49, 0.86). In 600 women aged 63 or older from the Framingham OA Study, women who ever used HRT for more than two years showed a one third lower prevalence of radiographically defined knee OA, but the difference from non-users was statistically non-significant.6 This inverse association was stronger looking at women with bilateral OA only (OR=0.52; 95% CI: 0.25, 1.09). In contrast with the cross sectional studies, the exposure in the Framingham Study was assessed before the outcome making a bias of reversed causality less likely.

Two recent population based prospective studies also suggested a moderate protective effect of HRT regarding the incidence of knee OA, but the confidence intervals around these estimates were wide and included the null value. In an eight year follow up of the Framingham cohort, a possible reduction of risk of incident radiographically defined knee OA was found in current HRT users (OR=0.4; 95% CI: 0.1, 3.0).7 A four year follow up of the Chingford population was compatible with a protective effect of current HRT use on the development of knee osteophytes (OR=0.4: 95% CI 0.1, 1.4), but also with an increase in risk regarding the development of joint space narrowing (OR=1.9; 95% CI: 0.9, 4.1).8

HRT use was not associated with hand OA in the Chingford study.5 In this study, DIP and CMC OA were defined according to the Kellgren and Lawrence score and considered separately. Samanta et al observed no association between HRT and prevalent GOA, defined by Herberden's nodes and polyarticular interphalangeal OA, in a British case-control study.18

A recent case-control study did not find an association between current HRT use and incident cases of hip, knee and hand OA,9which was defined as radiographic OA according to the Kellgren and Lawrence score plus symptoms. However, a high OA incidence was found in new oestrogen users, and the authors concluded that the utilisation of medical services by new HRT users increases the likelihood of an OA diagnosis. A further case-control study found a slightly positive association between women who ever used ORT for less than five years and advanced symptomatic hip OA, which might reflect a possibly higher prescription rate of oestrogens to women with present hip pain.19

In the previous studies, women with OA were compared with women without OA. In contrast, participants of our study were selected according to a manifest OA of one hip or knee joint. This selection makes different access to medical care unlikely. The selection of our study participants who all had advanced OA in one hip or knee joint is 1ikely to be independent of the different OA patterns, the laterality or generalisation. On the other hand, results of our study with participants preselected by the presence of advanced OA in at least one joint may not be generalisable to early forms or incident OA.

OA patterns in our study were classified radiographically after documentation of a very good (hip and knee joint) or sufficient (GOA) intra-rater and inter-rater reliability. Classification of the participants into patients with unilateral or bilateral OA was based on the radiograph of the joint opposite to the one being replaced. The classification into generalised or localised OA is equivalent to the definition of the Chingford study for knee OA, where GOA was defined by the presence of OA in both finger joints (DIP and PIP) and carpometacarpal joint in addition to knee OA.16 This definition was extended to hip OA in our study, because the hip joints are—like the knee joints—big, weight bearing joints.11 ,20 Together with hip or knee OA, these women had radiological OA of at least three different joint groups. The overall prevalence of GOA might not be directly comparable to other studies using different radiographic gradings of hand OA, but this should not affect the validity of the internal comparisons (odds ratios) presented.

Detailed history of current medication use including hormone preparations was asked for by a trained physician and confirmed by medication packages brought to the hospital. An investigation of the Postmenopausal Estrogen/Progestin Interventions Trial showed a 95% agreement concerning the reporting of an ever use of HRT.21 As HRT use is socially well accepted it is unlikely that oestrogens are deliberately not reported in our study.

We controlled for a variety of possible confounders using multivariable logistic regression. We adjusted for age, body mass index, diabetes mellitus, gout, age of menopause, thiazide intake, hysterectomy status and smoking. Unlike other studies we did not control for bone mineral density because this may be on the causal pathway between ORT and OA—that is, oestrogen users are less affected by loss of bone mineral density after menopause than non-users and bone mineral density might be associated with the risk of OA.3 ,22 In our study, age was the main confounder of the association between HRT and different OA patterns. This results from the fact that HRT use decreases with age, while the prevalence of OA, especially GOA, is increasing.

A limitation of our study is that information was obtained for current regular medication during the past three months only. Hence, there was no information about past HRT use and the group of non-users may have included some women who have used HRT in the past. Their number should be very small, however, given that HRT use was very rare in Germany in the past. For example, in a national survey conducted eight years before our study, only 4.5% of the women between 45–80 years (mean age 58.1 years) were currently taking HRT.23 Therefore, possible bias attributable to missing information about past HRT use is probably small. One further possibility may be that some women stopped HRT intake before surgery because of anxiety about an increased risk of thrombosis, but it is unlikely that they stopped oestrogen medication three month before surgery, which was the time period hormone use was asked for. In current users of HRT, we had no information about the type and duration of use of different preparations in the past in case of a previous change in preparation, nor about compliance. Therefore, the results regarding duration of use have to be interpreted keeping this limitation in mind. Concerning the duration of use, a mean of a five year use might be too short to see an effect of HRT on a slowly progressive disease like OA. Furthermore, we could not investigate the time sequence between HRT and OA patterns because of the cross sectional study design. Therefore, the possibility of an OA manifestation before the beginning of HRT use cannot be ruled out. Besides, the possibility that HRT may be used by women to relief symptoms of painful joints cannot be excluded.

In summary, we did not observe an independent association between HRT and either generalised or bilateral OA in postmenopausal women with advanced OA of the hip or knee joint. Despite its limitations, our study does not support the hypothesis that HRT could act as a systemic protective factor against OA.