Aromatase inhibitor-induced musculoskeletal symptoms in foot and ankle surgery

Approximately 4,700 Danish women are diagnosed with breast cancer annually [1]. In the majority, either oestrogen receptor or progesterone receptor is overexpressed, promoting the development of breast cancer [2]. Thus, various hormone receptor-targeted therapies such as aromatase inhibitors (AI), e.g., anastrozole and letrozole, have been developed [3]. In postmenopausal women, AIs are the cornerstone for managing hormone receptor-positive breast cancer [4].

With the continually improving long-term prognosis for breast cancer patients, there is a growing focus on survivorship and quality of life for breast cancer survivors undergoing up to five years of antihormone treatment. AI treatment increases overall survival and is generally considered to have a well-tolerated side effect profile [5]. However, even third-generation AIs have been recognised to cause significant musculoskeletal symptoms affecting patients’ quality of life and consequently causing frequent discontinuation of therapy [4, 6, 7].

Described musculoskeletal symptoms of AIs include arthralgias, myalgias, joint stiffness and tendinopathy - and approximately 70% of the patients treated with AIs in oestrogen receptor-positive and/or progesterone receptor-positive breast cancer presented arthralgias or myalgias [6]. The constellation of these musculoskeletal symptoms has been termed the AI-associated musculoskeletal syndrome (AIMSS). Recent studies suggest that abrupt oestrogen withdrawal is a key factor in its mechanism of development [4, 6]. Similar symptoms are described for postmenopausal patients with sudden withdrawal of menopausal hormone therapy [8].

Among the three types of AI, letrozole is the most commonly used in Europe, followed by anastrozole and exemestane [9]. Patient-reported outcomes confirm similar safety profiles for these treatments, although exemestane is linked to more side effects. For letrozole, the second most frequently reported adverse event was arthralgia [10]. Up to 70% of patients with arthralgias and myalgias reported a maximum pain intensity between 5 and 7 on a scale ranging from 1 to 10 [6]. Furthermore, 17-51% of patients report AIMSS-related pain localised in the ankles/feet [7, 11].

In this report, we describe illustrative cases of AIMSS referred to the Section of Foot and Ankle Surgery at Bispebjerg and Frederiksberg Hospital and Bornholm Hospital, Denmark to raise awareness of the syndrome as a diagnostic pitfall.

Methods

Five cases of suspected AIMSS were referred and evaluated by a foot and ankle surgeon in our outpatient clinics at Bispebjerg Hospital and Bornholm Hospital over a 40-month period. The exact location of complaints varied, but presentations were overall comparable. Informed consent was obtained for all potential cases, and electronic patient journals of all potential cases of AIMSS were examined.

Trial registration: not relevant.

Results

See Table 1 for anamnesis, objective findings and paraclinical tests, along with treatment and outcome of the five cases.

Discussion

AIMSS is a widely reported phenomenon, and suboptimal compliance with AI adjuvant therapy due to inadequately managed AIMSS remains a challenge and a major unmet need. To our knowledge, no specific literature on this topic exists, even though this diagnosis is very relevant for oncologists, rheumatologists, orthopaedic surgeons and general practitioners. In our opinion, significant improvements in patient treatment can be achieved with recognition of AMISS as a possible differential diagnosis in cases of refractory pain after commencement of AI treatment.

Some studies refer to these symptoms as arthralgia syndrome and AI-induced arthralgia. However, more recently, the term AIMSS has been introduced to describe the constellation of joint pains [12-15].

The lack of a formally accepted definition for AIMSS remains a major challenge; however, there is agreement about the relation between the onset of symptoms and the start of AI therapy, as well as the relation between improvement in symptoms or spontaneous symptom resolution after cessation of AI treatment. Symptom onset can range from a couple of weeks to more than ten months, with a median of 1.6 months [12-14, 16].

All five patients in this case series were referred to our foot and ankle surgeons by a general practitioner for severe foot and ankle pain consistent with AIMSS. In all cases, there was also a history of pain in other joints, and symptom onset consistently occurred after initiation of treatment with AI medication, which is also in line with the general definition of AIMSS. The five cases mentioned above, are - in our opinion - good examples that correspond with recent studies, which report the frequency of arthralgia associated with anti-oestrogen treatment to fall in the 30-70% range [4, 6].

In these cases, the suspicion of AIMSS as the most likely diagnosis was based on its temporal relationship to the initiation of antihormonal treatment. The variation in symptom relief after treatment breaks or termination could be attributed to insufficient duration of treatment breaks or premature referral to surgical evaluation before the effect of termination of treatment had been achieved. However, we acknowledge that there is no consensus in the existing literature on the necessary duration of treatment breaks for effective symptom relief. Niraveth et al. suggested that joint pain improves and may even resolve within as little as two weeks of stopping AI therapy. However, this was not found in any other published study [14].

It was also hypothesised that anti-oestrogen treatment might enhance the intensity of arthralgia already present or trigger other diseases, e.g., osteoarthritis, suddenly making it symptomatic at the time treatment was initiated. Furthermore, the secondary criteria, e.g., morning stiffness and improvement with use or exercise, were not described as related to foot and ankle pain in the charts of any of the reported cases.

Our series reports similar cases, which, in our opinion, were worsened by a lack of awareness and general knowledge. Even though our five cases cannot establish beyond a doubt that AMISS was the cause of their symptoms, they illustrate typical clinical scenarios in which AMISS could be suspected. One cannot draw firm conclusions from this material; however, it may increase awareness of AIMSS as a differential diagnosis in cases of spontaneous and/or worsening pain in the foot and ankle. Awareness may improve patient management and help avoid unnecessary or potentially harmful procedures and treatments.

It is important to note that this case series has several important limitations. One of the unavoidable drawbacks is that most patients with this condition are generally in an age bracket where it is common to encounter multiple concurrent degenerative musculoskeletal conditions. Similar symptoms are also described as a part of the musculoskeletal syndrome of menopause [8]. Hence, there is a risk that we may treat pre-existing conditions that are not necessarily the cause of the patient's actual symptoms.

We also wish to emphasise that AIMSS is not yet fully understood and further research into its mechanisms and treatment, as well as formal diagnostic criteria for this syndrome, is needed.

Conclusions

AIMSS affects the joints of the foot and ankle and may cause discomfort and pain near the start of AI therapy. All five cases reported debuted with severe foot or ankle pain after the patients initiated AI for breast cancer. Poor physician attention and subsequent lack of patient information of this known adverse effect of AI may result in redundant, time-consuming, costly and potentially harmful diagnostic procedures and treatments. We hope this report will raise awareness of AIs as a cause of spontaneous and refractory pain in the foot and ankle.