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Rheumatology Advance Access published online on November 10, 2008
Rheumatology, doi:10.1093/rheumatology/ken390
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Review

Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review

B. M. de Klerk1, D. Schiphof1, F. P. M. J. Groeneveld1, B. W. Koes1, G. J. V. M. van Osch2,3, J. B. J. van Meurs4 and S. M. A. Bierma-Zeinstra1

1Department of General Practice,2Department of Orthopaedics,3Department of Otorhinolaryngology,4Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

Correspondence to: B. M. de Klerk, Department of General Practice, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: b.deklerk{at}erasmusmc.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Supplementary data
 References
 
Above the age of 50 yrs, the incidence of OA rises steeply in women but less in men, suggesting an association with changes in female hormone levels in the menopause. This systematic review summarizes the evidence on the assumed association between exogenous hormone use and OA. Medline was searched up to March 2008 for articles assessing associations between OA of hand, hip or knee and menopause-related aspects. Methodological quality of the studies was assessed systematically. The results were summarized in a best-evidence synthesis. Nineteen studies on exogenous hormone use are included. Limited evidence was seen for a protective effect of unopposed oestrogen use for incidence of hip replacement/joint replacement, and a protective trend for incident radiological OA (ROA) of the knee. In prevalence studies, conflicting evidence was observed for hormone replacement therapy (HRT) use with DIP ROA and ‘any joint OA’, and oestrogen use with clinical knee OA. We found limited evidence for a significantly increased risk by using HRT for clinical hip OA and a significant protective effect of long-term unopposed oestrogen use for hip ROA. For all other relations studied no associations were found. Heterogeneity between the hormones used and outcome measurements made statistical data pooling impossible. The assumed relationship between the exogenous hormone use and OA was not clearly observed in this review. The relationship is perhaps too complex, or other aspects, yet to be determined, play a role in the increased incidence in women aged over 50 yrs. However, there is some evidence of a protective effect of unopposed oestrogen use for hip OA.

KEY WORDS: Menopause, Osteoarthritis, Hormone replacement therapy, Oestrogen


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Supplementary data
 References
 
OA is a growing problem among the elderly in western societies and causes pain and disability. In addition to the burden of physical discomfort, the enormous costs for society [1–3] are expected to keep rising due to increasing life expectancy [4]. Prevalence of OA is higher in women than in men [5, 6] and incidence rises with age.

The increase of OA incidence is higher in women than in men after the age of 50 yrs [7], which is puzzling. As early as 1925, Cecil and Archer [8] reported an apparent close connection between OA and the menopause based on a study of 50 female cases. Oestrogen levels are lower in menopausal women than normal menstruating women, which suggests that oestrogen may be an important regulator of OA [9]. Results of studies on the possible association between OA and menopausal aspects and exogenous hormone use are not consistent, and a complete overview on the present level of knowledge on this relationship is lacking. Insight in the association between OA and exogenous hormone use may contribute to the formulation of a high-risk profile for OA development and a better understanding of OA aetiology.

The aim of this systematic review is to gain insight in the current stage of knowledge on the association between OA and exogenous hormone use.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Supplementary data
 References
 
Identification of studies
The articles were identified by systematically searching the database of Medline up to March 2008. Osteoarthritis, oestrogen, HRT, menopause and equivalents of these words were used as keywords (see Appendix I available as supplementary data at Rheumatology Online). The search was extended by screening the reference lists of all included studies and relevant reviews.

A study was included when all the following criteria were fulfilled: (i) the article presents original data on a human study population, (ii) disease of interest is incident or prevalent OA of the hand, hip or knee (tibiofemoral OA), (iii) women with and without OA are compared in the study, (iv) the study reports on exogenous hormone use related to OA presenting odds ratios (ORs), relative risks (RRs), P-values or data extended enough for one of these to be calculated, (v) studies on genetics of menopause-related determinants are excluded, (vi) the article was written in English, Dutch, German, African, Norwegian, Danish or Swedish and (vii) the full-text article was available. Two independent researchers checked the abstracts on the aforementioned criteria.

Methodological quality
The methodological quality of the included articles was assessed using a scoring list based on the scoring list used by Scholten-Peeters et al. [10] and Lievense et al. [11] (see Appendix II, with specifications in Appendix III available as supplementary data at Rheumatology Online). The list was modified to cover the topic of our review and concerns both the internal validity and informativeness of the article.

All articles were scored independently by two reviewers (B.M.d.K. and D.S.). In case of disagreement, consensus was aimed for. If consensus was not achieved, a third reviewer (S.M.A.B.-Z.) gave final judgement.

Not all items were applicable for every study design and the number of relevant determinants differs between studies. For example, for a prospective cohort study specifications on loss to follow-up should be described, while this item is not applicable in a retrospective case–control or cross-sectional study. Therefore, the maximum score of each study (100%) was based on the number of items applicable for that particular study. All other items were scored identical for all study designs, scoring positive (+), negative (–) or not given (?). Positive scores were summed up to indicate an overall internal validity score.

Evidence synthesis
Evidence from homogeneous studies outcomes was pooled. In case of heterogeneity, we refrained from statistical pooling and performed a ‘best-evidence synthesis’ [11–14].

The studies were divided into subgroups according to the study design. A study was considered to be of high quality if the methodological score was ≥60%. The best evidence synthesis was performed using the following levels of evidence [14, 15]:

  • Strong evidence: consistent findings (>75%) in multiple high-quality studies.
  • Moderate evidence: consistent findings (>75%) in one high-quality study and some other low-quality studies or multiple low-quality studies.
  • Limited evidence: only one high-quality study.
  • Conflicting evidence: inconsistent findings in several studies of equal quality.
  • Insufficient evidence: less than 2 low-quality studies available.
  • No evidence: provided when no studies could be found.
In case of a sufficient number of included studies (N = 10), a sensitivity analysis [binary logistic regression analysis (SPSS-11.0.1, SPSS Inc, Chicago, Illinois, USA)] was performed. In case of an insufficient number of included articles, differences were screened by eyeballing methods.

Data extraction
Two researchers (B.M.d.K. and D.S.) independently collected characteristics of the included studies. The characteristics covered the study design, study population, determinants and type and severity of OA. If specified in the underlying study, we reported for each study whether unopposed oestrogen or opposed oestrogen (a combination therapy of oestrogen plus progesterone) was used. When only oestrogen replacement therapy was mentioned, we used the term ORT. When only ‘hormone use’ was mentioned or when unopposed and opposed oestrogens were analysed together, we used the term hormone replacement therapy (HRT).

RRs or ORs were extracted. The following definitions were applied for dichotomous outcomes:

  • 95% CI does not include 1.00: significant outcomes: association present.
  • OR or RR > 1.00: significantly increased risk; OR or RR < 1.00: significant protective effect.
  • 95% CI includes 1.00: non-significant (NS) outcomes: no association present.
  • OR or RR < 0.5; 95% CI includes 1.00: NS protective; OR or RR > 2.0; 95% CI includes 1.00: NS increased risk; 0.5 > OR or RR > 2.0; 95% CI includes 1.00: No relation.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Supplementary data
 References
 
Identification and selection of the literature
The systematic search initially resulted in the identification of 1064 references in Medline, which were screened on title and abstracts. This lead to a full-text reading of 61 articles of which 25 met our inclusion criteria. Six of the 25 initially included articles were subsequently excluded: three studies did not specify the joint affected by the OA [16–18], one study reported on patello-femoral OA only [19], one study did not specify a cut-off point for OA presence [20] and for one study we were unable to calculate relevant outcomes [21]. Screening the reference lists of the selected studies did not add any new studies. Finally, 19 studies were included in this systematic review. Figure 1 shows the flow chart of this selection process.


Figure 1
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  		FIG. 1. Flow chart of the selection process.

 
Methodological quality assessment
The two reviewers each scored 343 items from the 19 studies included and initially agreed on the quality score of 252 items (73%, {kappa}: 0.55). Disagreements of 75 items were solved in one consensus meeting and 16 items were presented to the assigned co-author for final judgement. The average rating was 62.5% (range 20.0–73.3%). Table 1 gives a description of the characteristics of the included incidence studies and prevalence studies. The size of the study populations included in this review ranged from 120 to 16 049 (median = 678).


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  		TABLE 1 Characteristics of the included studies

 
Four of six studies on incidence included met the criteria for high quality [22–25], as well as 10 of 13 prevalence studies [26–35]. The quality scores of the included studies are presented in Appendix IV available as supplementary data at Rheumatology Online.

Heterogeneity
All, but one [24], included studies are observational and heterogeneous with regard to the determinants and outcome measures and study population, making pooling impossible. Even within the studied determinants, heterogeneity on these points was too large to justify pooling. Therefore, we refrained from pooling and performed a best evidence synthesis.

Results of the studies included
In the description of the results a subdivision is used in type of OA: radiological OA (ROA), indicating radiological changes only and clinical OA (COA), where both radiological changes and symptoms are present in the same joint. COA includes total replacements of hip (THR), knee (TKR) or joint (TJR, hip or knee).

Description of the studies included
Nineteen studies on exogenous hormone use were included [22–40]. Four studies have a prospective cohort design [22, 23, 36], of which one randomized controlled trial [24]. There are six retrospective [25, 34, 35, 37, 38, 40] and nine cross-sectional [26–33, 39]. Nine studies are nested in larger cohorts: two retrospective studies [25, 37] and seven cross-sectional studies [27–31, 33, 39].

Incidence studies: HRT
Six studies report on OA incidence (Table 2). An association with incidence of hand COA was only examined in the Fallon Community Health Plan [25], where no evidence of an association with ever usage of oestrogen was seen.


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  		TABLE 2. Results included studies on OA incidence

 
Also, hip OA was studied in the Fallon study where an NS protective effect of ever oestrogen use and incident hip COA was found in 27 case–control pairs. In the RCT of the Womens's Health Initiative (WHI) [24], a significant protective effect of unopposed oestrogen use for total hip replacement (THR) was found in hysterectomized women. While in the same study, use of opposed oestrogens (a combination of oestrogen plus progestin), which is used in non-hysterectomized women, showed no such significant effect. Researchers in the Study of Osteoporotic Fractures (SOF study) [36] found no relation between current oestrogen use and incident hip ROA or THR.

In the Chingford study [22] as well as the Framingham [23], Fallon [25] and WHI studies [24], no significant associations were seen between unopposed oestrogen [23, 24] or HRT [22, 25] usage and incident knee ROA or total knee replacement (TKR). For current use of mainly unopposed oestrogens in the Framingham study [23] and for current use of HRT in the Chingford study [22], a NS protective effect was found.

In studying ‘any joint COA’ (hip or knee), a significant protective effect of unopposed oestrogen use was seen in the WHI study for total joint replacement in hysterectomized women [24]. In the same study, this effect was not observed in non-hysterectomized women (using opposed oestrogens) or in the Fallon study [25].

Prevalence studies: oral contraceptive use and HRT
Thirteen studies report on OA prevalence (Table 3). None of the studies found a significant association for the use, or duration of use, of (oral) contraceptives with OA; all outcomes (ORs) ranged from 0.57 to 1.60 indicating ‘no relation’.


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  		TABLE 3 Results included studies on OA prevalence

 
Four studies on prevalence of hand OA were included in this review [26, 27, 29, 31]. In the Rancho Bernardo study [31], as well as in a population of Tasmanian women [26], a significantly increased risk by oestrogen use for hand COA (presence of Herberden's nodes) was seen. No associations were found with ROA or COA of DIP and CMC joints.

In the Rancho Bernardo study [31] a significantly increased risk for COA of the hip was also seen. While for hip ROA, the SOF study [28] found a significantly protective association with current oestrogen use and current use for ≥10 yrs. In this study, 82% of the women used unopposed oestrogenes; in subgroup analyses for those who used opposed oestrogens the protective effect disappaered. Dennison et al. [38] and Vingard et al. [35] both found no association between ever oestrogen or HRT use and hip COA.

Prevalence of knee OA was examined in seven studies. The Chingford study [29] found current use of HRT to be protective of knee ROA, while Sowers et al. [27] found current HRT use to be significantly increasing the risk of knee ROA in the highest joint score, but not for knee ROA Kellgren and Lawrence score ≥2. Sandmark et al. [34] found ever usage of oestrogen to be significantly increasing the risk of knee COA. Others found ever use of oestrogen to be not associated with knee ROA [19, 29, 33], or knee COA [30, 31]; one of these studies [33] clearly stated that mostly unopposed oestrogens were used.

In studying ‘any joint OA’ (hand, hip or knee) with oestrogen use, one study found a significantly increased risk [31] and calculating with data from Schneider [39] we found ‘no relation’; whereas both studies describe the Rancho Bernado study population. Samanta et al. [40] also found no association for this same relation in their study.

Finally, ‘duration of use’ was evaluated in four studies. One study found a dose–response effect for duration of HRT [31], with a similar dose–response pattern for hand, knee and hip COA. They found that, among oestrogen users, women with OA had used oestrogen significantly longer than women without OA. Three other studies found no such significant relations between duration of HRT/ORT and knee ROA or COA [28, 33, 37].

A sensitivity analysis was performed using binary logistic regression analysis (SPSS-11.0.1). Studies were compared on adjustment for age, BMI, BMD, assessment manner of OA (clinical or radiological), funding source and menopausal status of the population. No clear differences in outcomes of the determinants were found.

Evidence synthesis
Incidence studies
Limited evidence for a significant protective effect of unopposed oestrogen use for incidence of THR and TJR was observed in hysterectomized women. In non-hysterectomized women, using opposed oestrogens, limited evidence of no association with THR or TJR was found.

For knee ROA, limited evidence for no association was seen for both hysterectomized and non-hysterectomized women. However, it should be noted that another study in which most women used unopposed oestrogens, an NS protective effect for knee OA was found, and in two more studies an NS protective effect for knee OA and hip OA, respectively.

For hand OA only one study was available, resulting in limited evidence for no association.

Prevalence studies
The evidence for DIP ROA was conflicting for both ever and current HRT use. For CMC ROA, there was strong evidence for no association. For hand COA and the presence of Herberden's nodes, the evidence was strong in the direction of a significantly increased risk.

Limited evidence for a significantly increased risk due to HRT use was found for hip COA. For hip ROA and current use of HRT no relation was seen for short-term use (limited evidence); but for long-term use (mainly unopposed oestrogens), the evidence was limited for a significant protective effect. For ever use, strong evidence of no relation was found, irrespective of duration of use.

Conflicting evidence was seen for a relation between ever oestrogen use with knee COA. Ever use of HRT and knee ROA was found to be not related with strong evidence, while for current use conflicting evidence was seen. For the duration of HRT use (long term or short term) in knee ROA limited evidence was found for no relation. And finally for ‘any joint OA’ with HRT use conflicting evidence was seen.


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Supplementary data
 References
 
The assumed relationship between exogenous hormone use and OA of the hand, hip or knee was not clearly observed. Most evidence points in the direction of no relation between OA of hand, hip and knee and exogenous hormone use, or the evidence remains conflicting. However, only for the outcomes in incidence of THRs there seems to be a trend of a limited protective effect in women using unopposed oestrogen.

There have been other reviews on this subject in the past by Wluka et al. [41] in 2000, including 11 studies, and by Hanna et al. [42], and the American College of Obstetricians and Gynecologist [43] (ACOG), both in 2004 and including 10 studies. Based on our Medline search, we included almost twice as many studies in our systematic review (N = 19), while excluding some of the studies included in the reviews of Wluka, Hanna and/or the ACOG due to not complying with our inclusion criteria [21, 44–46]. Finally, leading to a more comprehensive and up-to-date overview on the subject.

The use of exogenous hormones is intertwined with other menopausal aspects like hysterectomy and menopause-related health complaints, making it difficult to study the influence of the hormones used and possibly leading to confounding. Data collection in the studies was sometimes questionable due to limited information, possibly contributing to why no hard evidence was found. For example, studies were not always clear on the type, dosage and duration of hormones used and the reason for using HRT is often not specified. HRT users are more likely to have low BMD and osteoporosis, which may protect these individuals from developing OA [16]. It would be expected that if female hormones have the alleged impact on OA development, more significant outcomes would be found in literature.

Also, in the case–control studies there are concerns about the validity of identification of cases. It is imaginable that women using hormones, and therefore visiting physicians more often than women who do not, are more likely to have their complaints diagnosed as OA, simply because complaints are more often presented to physicians. This could lead to a false-positive correlation between hormone use and OA in retrospective case–control studies. Considering this, it may not be completely fair to compare women with ovariectomy and those with natural menopause. Our quality assessment shows that in case–control studies, the OA assessment manner was often not identical for cases and controls, leading to possible bias. On the other hand, if considering only the data from study designs where OA assessment was identical for both study groups, the evidence remains conflicting. Also, from animal studies it is shown that removing the ovaries is not equal, concerning hormonal influence, to a natural menopause [47, 48].

As stated above, several studies were unclear about what type of HRT was used. Only four studies [23, 24, 28, 33] clearly stated that unopposed oestrogens were used and showed mainly a protective effect. Unfortunately, because the exact distribution of type of HRT remained unclear in most studies, we cannot firmly conclude that unopposed oestrogens protect against OA.

The search performed was extended in used keywords, as was the applied methodological quality assessment. Although we put much effort in identifying relevant articles, our search might have some limitations. Some relevant articles may have been missed because they used other keywords, had unclear abstracts, were not written in English, Dutch, German, South African or any of the Scandinavian languages, not specified the OA-affected joint or were not indexed in Medline. However, we do not expect to have missed articles by using only this one database, because an identical search performed in EMBASE up to March 2006 did not yield new articles, and all references of the included articles were checked.

In excluding studies on GOA, without specification of outcomes on hand, hip or knee joint, we may have lost relevant data. However, in analysing the excluded studies on HRT use and GOA, two studies found HRT use was protective [16, 17], another found an increased risk [49], and two others found no relation [18, 44]. Also, no association between HRT use and frequent knee pain was found in the HERS study [50]. Therefore, we postulate that the evidence for the assumed association between HRT use and OA would remain conflicting, even after including these studies.

In the evidence synthesis used in this review, all NS outcomes were interpreted as evidence of no relationship between exogenous hormones and OA. Still, it is possible that an association is present, but it could not be found using the applied study designs and corresponding sample sizes.

Despite the limitations of a best evidence synthesis compared with a more quantitative synthesis, we argue that the use of this systematic approach is appropriate. With scoring the quality of the included studies and defining levels of evidence, we give the reader insight in the process of reaching conclusions.

Due to the large heterogeneity in study population and determinant and outcome measures, statistical pooling data were not feasible. For example, effects of hormones on disease may affect symptoms, structure or both and may have different effects on different joints. In this review, the focus of OA assessment (e.g. clinical vs radiological) and studied joints differ between studies. In case of such large differences in outcome measurements, it is preferable to refrain from pooling and divide studies into smaller groups in a best evidence synthesis.

Influence of exogenous hormones on OA is also investigated in animal studies. Animal models on ovariectomy, for example, are frequently used since the 1980s, and well accepted in osteoporosis research. Because both bone and cartilage are sex-hormone sensitive, ovariectomy was expected to result in cartilage changes as well, and this became a topic of study in the last decade. These studies on various species [51–57] showed that ovariectomy resulted in increased cartilage degradation as demonstrated histologically by surface erosions, biomechanically by changed intrinsic material properties, or biochemically measuring cartilage degradation marker (CTX-II) in urine. Oestrogen replacement in these models reduced the OA changes [51, 53]. However, a recent systematic review on animal models for OA in conclusive evidence was found for an association of OA with ovariectomy or oestrogen treatment [58].

For future research on OA and exogenous hormone use, we suggest to at least adjust for age and BMI. We recommend to specify the type, dosage and duration of the HRT used and to adjust for BMD, since HRT is often used for women with osteoporosis, which could confound outcomes. However, prescription of HRT (combination oestrogens with progesterone) is limited nowadays because of increased risk of breast cancer [59]. A design with oestrogen substitution alone might have no effect on breast cancer, but this regimen is nowadays only used for hysterectomized women [60]. We hoped that gaining insight in the association between OA and exogenous hormone use would contribute to the formulation of a high-risk profile for OA development and a better understanding of OA etiology. Unfortunately much remains unclear. The fact remains that incidence and prevalence rises quickly in women after the age of 50 yrs. Possibly the relationship between exogenous hormones and OA of hand, hip and knee is too complex to appear in epidemiological research as such, or other aspects, yet to be determined, play a role in the increased incidence in women after the age of 50 yrs.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   Supplementary data
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary data
References
 
Supplementary Data are available at Rheumatology Online.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary data
 References
 

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Submitted 22 April 2008; revised version accepted 8 September 2008.
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B. M. de Klerk, D. Schiphof, F. P. M. J. Groeneveld, B. W. Koes, G. J. V. M van Osch, J. B. J. van Meurs, and S. M. A. Bierma-Zeinstra
No clear association between female hormonal aspects and osteoarthritis of the hand, hip and knee: a systematic review
Rheumatology, September 1, 2009; 48(9): 1160 - 1165.
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