Variations in the incidence of osteoarthritis occur according to local and systemic factors. In addition to local factors such as joint injury, obesity and occupation, the most significant increase is seen in older women who are three times more likely to be affected than men of a similar age.1
Epidemiological studies investigating the link between osteoarthritis and oestrogen have reported two main findings, first that onset of the menopause is associated with increased osteoarthritis incidence and severity, and second that hormone replacement therapy may reduce this effect. Oestrogen receptors α and β have been found in chondrocytes from both healthy and osteoarthritic joints. Two in vitro studies have demonstrated in a model of oxidative stress that cultured chondrocytes are protected by physiological doses of 17β-oestradiol in a dose-dependent relationship.2 3
A recent systematic review of 11 animal studies attempted to summarise the effect of ovariectomy and oestrogen therapy on cartilage.4
However, the authors found the evidence inconclusive. A number of the studies used immature animals and a more convincing relationship between ovariectomy and cartilage changes was seen when these experiments were excluded. Animal studies are extremely limited in their application to humans, especially as ovariectomy will cause a change in several hormones and does not directly reflect the physiological changes during the menopause.
The involvement of oestrogen in the homeostasis of joint tissues has been widely described, and it has been inferred that such protective effects will be reduced or lost as a result of the menopause. However, the most recent published in vivo research in humans remains inconclusive. The most recent systematic review found no clear evidence for an association between hand, hip and knee osteoarthritis and female serum hormonal levels, specifically assessing the duration of the fertile period, endogenous hormones, age at menarche/menopause, menopausal status, years since menopause and surgical menopause.5
A similar review by the same authors studied the link between exogenous hormone use and osteoarthritis of the hand, hip and knee, and again no evidence of any association was identified. However, this paper did identify that women using unopposed oestrogen therapy had a lower incidence of total hip replacements, and the authors described this as a possible protective effect in hip osteoarthritis.6
A recent study assessed the potential association between radiographic evidence of hand osteoarthritis and single-nucleotide polymorphisms in oestrogen receptors α and β, which have been associated with osteoarthritis in other joints. However, no significant relationship was identified.7
Here we report a case in which the global systemic reduction in oestrogen as a consequence of anastrozole therapy was associated with a profound inflammatory exacerbation of osteoarthritis but specific oestrogen receptor antagonism controlled the flare. This finding suggests that the osteoarthritis flare in this patient may have been due to the effect of reduced levels of oestrogen activity through non-tamoxifen dependent pathways. This supports the link between oestrogen and osteoarthritis, which has been so widely described in epidemiological studies but remains difficult to demonstrate in controlled studies.
Arimidex (anastrozole) is an aromatase inhibitor which acts by inhibiting the biosynthesis of oestrogens from androgens, as oestrogens have a proliferative effect on oestrogen-dependent breast tumours.8
Both arthralgia and osteoporosis are reported side-effects of anastrozole therapy, although further research into the pathophysiological mechanisms involved is required.
Tamoxifen is a selective oestrogen receptor modulator (SERM) used as an alternative adjuvant therapy for oestrogen receptor positive breast cancer. It has two major metabolites, N-desmethlytamoxifen and trans 4-hydroxytamoxifen. Trans 4-hydroxytamoxifen has been found to show oestrogenic activity, while its side-chain is antioestrogenic.9
Additionally, it is well demonstrated that SERMs reduce cartilage damage in ovariectomised animals.10
It is noteworthy that tamoxifen has been found in studies to increase bone mineral density and reduce numbers of fractures, thought due to its oestrogen-agonist effects.11
Arimidex showed the opposite effect with a reduction in bone mineral density.12
As far as the authors are aware, this is the first case in the literature to describe inflammatory osteoarthritis precipitated by Arimidex but resolved with tamoxifen. Improved understanding of the pathophysiological mechanisms involved in osteoarthritis in patients on treatment with oestrogen modifying agents may improve our understanding of the mechanisms involved in peri- and post-menopausal osteoarthritis. This could potentially lead to specific therapeutic targets to reduce disease progression in postmenopausal women who are burdened with osteoarthritis.
- Osteoarthritis is a significant cause of morbidity, affects three times as many women as men and currently has limited treatment options to alter disease progression.
- It has long been described that many women experience a flare of their osteoarthritis during the postmenopausal period, as oestrogen levels fall; however, the pathophysiological mechanisms remain poorly understood.
- We report a case where global systemic reduction in oestrogen due to Arimidex caused a flare in osteoarthritis, but tamoxifen, a specific oestrogen receptor antagonist, controlled the flare.
- Although further case series are needed, this case highlights the potential role of oestrogen modulation in the exacerbation of osteoarthritis and, if demonstrated in larger series, may direct future research towards specific oestrogen receptors rather than simply assessing systemic oestrogen levels.