Introduction
An aromatase inhibitor (AI) is a type of medication that stops the production of estrogen. This type of medication is the preferred treatment for hormone-receptor positive breast cancer in postmenopausal women. Since AIs cannot stop the ovaries from making estrogen, they are mostly used to treat postmenopausal women. The SOFT (Suppression of Ovarian Function Trial) study demonstrated that premenopausal women with hormone-receptor positive breast cancer could also be successfully treated with an AI if their ovarian function was suppressed. Ovarian suppression included either 5 years of triptorelin, surgical removal of the ovaries, or ovarian radiation. AIs have been compared with tamoxifen, a selective estrogen receptor modulator. AIs and tamoxifen are both hormone therapies, but act in different ways. AIs lower the amount of estrogen in the body by stopping certain hormones from turning into estrogen, while tamoxifen blocks estrogen receptors on breast cancer cells. Hence, estrogen is still present in normal levels with tamoxifen use, while estrogen levels are low with the use of AIs. AIs are preferred for the use of hormone-receptor positive breast cancer in postmenopausal women over tamoxifen because studies have shown more benefits, reduced risk of cancer recurrence, and fewer side effects. Serious side effects of tamoxifen in postmenopausal women include endometrial cancer because tamoxifen acts as an antiestrogen in breast tissue but acts like estrogen in the uterus. This can stimulate the uterine lining to grow and increase the risk of endometrial cancer in postmenopausal women. AIs also have their side effects that can have an effect on a patient’s quality of life and medication compliance. Their side effects include joint and muscle pain, osteoporosis, menopausal symptoms, hot flashes, vaginal dryness, and increased blood pressure. The arthralgia symptoms sometimes dominate patients’ daily lives, and it is important to educate these patients on the necessity of exercise and rehabilitation.
Etiology and Pathogenesis of Aromatase Inhibitor Musculoskeletal Syndrome
Estrogen Deprivation
The musculoskeletal side effects of AIs, including the arthralgia, myalgia, and stiffness, have been termed aromatase inhibitor musculoskeletal syndrome (AIMSS). The etiology of the syndrome is not well understood but is based off a few theories. Estrogen deprivation has been hypothesized as the major cause of AI arthralgia. It is unclear if the arthralgia is due to systemic or localized estrogen deficiency. Studies have shown that estrogen has chondroprotective effects by decreasing collagen degradation. Also, estrogen-based therapy has been associated with a reduced incidence of knee osteoarthritis and a reduced incidence of joint pain and swelling. In an animal study, mice with surgically removed ovaries demonstrated accelerated cartilage turnover, which was presumed to be linked to their decreased amount of estrogen. Since AIs stop the production of estrogen and estrogen decreases collagen and cartilage degradation, it can be inferred that this can be associated with the side effect of arthralgia.
Estrogen also has a natural antinociceptive property, meaning it blocks the detection of pain. This pathology is explained by opioid-containing neurons in the spinal cord which contain estrogen receptors. Hence, patients taking AIs may also feel an increased sensation of pain which contributes to their arthralgia.
Lastly, there have been many studies in rheumatology that found that drops in estrogen causes cytokines to be released in high levels, which may accelerate bone loss. Research has demonstrated that synovial cells express aromatase, and when aromatase induces the conversion of androstenedione to estradiol and estrone, IL-6 expression is decreased in the joint. IL-6 is both a pro- and antiinflammatory cytokine, but it has been linked to being one of the main causes of increased bone loss in postmenopausal women. Hence, when using an AI, a patient will have increased IL-6 expression, demonstrating another possible pathological explanation of AIMSS.
Tenosynovial Pathology
There have been several characteristic radiologic findings in patients with AIMSS. A key finding in some studies has been localized tenosynovial pathology to the hands and feet. In one study, 13 out of 28 patients with symptoms of AI arthralgia had evidence of tenosynovitis. In these patients, there was an absence of autoantibody development, which suggests more of a localized tenosynovitis instead of a systemic inflammatory process. There were also less complaints of lower back and knee pain, which are more common for postmenopausal pain, which suggested that this pathology was most likely not due to osteoarthritis seen in menopause.
Another study showed 12 patients on AIs who reported severe morning stiffness and pain in their hands and wrists, causing impairment in closing and stretching both the hands and fingers. Trigger finger and carpal tunnel syndrome were the two most common reported clinical signs. Both ultrasound and MRI were used to demonstrate the radiologic findings. Ultrasound results showed fluid in the tendon sheath that enclosed the digital flexor tendons, and MRI results showed an enhancement and thickening of the tendon sheath. These MRI results were found in all 12 patients.
A final study that suggested fluid retention within joints plays a key role in AI arthralgia showed that women, who were on AIs and also had chronic diuretic treatment for other medical conditions, were less likely to report muscle pains or stiffness.
Autoimmunity
Some studies show absence of autoantibody development in AIMSS, while others show patients with elevated antinuclear antibodies and rheumatoid factor concentrations. One study selected 30 patients with AIMSS and 22 controls without the syndrome. Serum samples were collected at baseline and during treatment which tested for multiple inflammatory cytokines and lipid mediators. The study found there were no statistically significant changes during AI therapy between cases and controls for any of the inflammatory markers tested. This study concluded that the syndrome is most likely not associated with a systemic inflammatory response, but a localized one.
Clinical Characteristics
AIMSS typically presents with symmetrical joint pain, stiffness, myalgia, and decreased grip strength. Almost all joints have been reported in research causing pain in AI arthralgia, but some studies have shown it most commonly targets the hands, knees, and back. It has also been shown to present with carpal tunnel syndrome, trigger finger, and De Quervain’s tendonitis. The onset of symptoms varies; however, the median time has been shown to be 1.6 months. This ranges with some patients noticing symptoms a couple of weeks into treatment, while others did not start to feel symptoms until 10 months. Symptoms also tend to be their highest at about 6 months.
Noncompliance
The pain and arthralgia that some of these patients face are so severe that these can lead to noncompliance of taking their AI. There have been several studies that demonstrate this. Among 437 patients using AIs, 47 prematurely discontinued their AI with an average of 29 months after initiation of therapy. Patients reported worsening joint pain, which they rated as a 4 or greater on the Brief Pain Inventory scale. A score of 0 meant no pain and a score of 10 meant the worse pain you can imagine. In this study, 11% of patients discontinued their therapy, with the number one cause being joint pain (57%). The musculoskeletal pain in these breast cancer patients was so debilitating that they would rather not finish their treatments than experience it.
Diagnosis
Currently, no objective diagnostic criteria for AIMSS exists. This causes variation in the diagnosis of AIMSS, and in its incidence, since providers may be using different criteria to define it.
An MRI is a diagnostic test that can demonstrate changes in AIMSS. MRI studies in patients taking AIs have shown tenosynovial changes and increased intraarticular fluid. Tenosynovial changes were defined as an increase in the amount of fluid in the tendon sheath or the thickening and enhancement of the tendon sheaths. Ultrasound can also show fluid in the tendon sheath. However, there does not have to be diagnostic test pathology to define AIMSS, since no definitive criteria exist.
Treatment
Medications
Medications can be used to try and treat the symptoms of AIMSS, but there is no true first line appropriate method identified as research is still in progress. Pain medications that can be used include acetaminophen, topical or oral nonsteroidal antiinflammatory drugs, and tramadol.
Glucosamine and chondroitin sulfate treatment showed moderate improvement in musculoskeletal symptoms after 24 weeks of treatment in patients with AI arthralgia.
A trial of duloxetine showed clinically significant improvement in pain scores in patients on AIs. Patients were treated with duloxetine for 8 weeks, and the results showed a 30% decrease in the average pain score over 8 weeks.
Calcitonin has been demonstrated to improve bone pain during AI treatment but did not have an effect on bone loss during the cancer treatment.
Role of Rehabilitation Medicine
The physiatrist and members of the rehabilitation team, which commonly includes physical and occupational therapists, can be of great help to minimize the pain and improve the function of patients with AIMSS. The physiatrist has expertise in musculoskeletal medicine and can diagnose and treat the pain associated with this condition using medications and injections. They can also prescribe and monitor an effective treatment plan that includes physical and/or occupational therapy. Physical therapy can help these patients improve their physical abilities and regain strength, while occupational therapy can focus on improving activities of daily living.
Exercise
Exercise has been shown to improve a patient’s musculoskeletal symptoms while taking an AI. One study demonstrated that 150 minutes per week of moderate intensity cardiovascular exercise and 2 days a week of resistance training provided a statistically significant improvement in the pain levels of patients with AI arthralgia.
Another study investigated whether postmenopausal women on AI therapy differed from healthy postmenopausal women when they compared their responses to the same exact aerobic and resistance training programs. The results demonstrated that postmenopausal women on AI therapy and healthy postmenopausal women demonstrated similar improvements in body fat mass and estimated lower body strength. One difference was that healthy postmenopausal women demonstrated an increase in upper body strength after 6 months, while postmenopausal women on AI therapy demonstrated an improvement after 9 months of training. Overall, the study concluded that postmenopausal women on AI therapy have the ability to adapt to the same regimen of resistance and aerobic training as healthy postmenopausal women. This shows the importance of a combined exercise program for the treatment of AIMSS.
Prophylaxis
In addition to arthralgias, women taking AIs are also at an increased risk for fractures. AI-associated bone loss is 2–4× greater than bone loss in physiological postmenopausal bone loss in women. Denosumab, intravenous and oral biphosphonates have been demonstrated to effectively prevent AI-associated bone loss in patients with breast cancer. The Adjuvant Denosumab in Breast Cancer Trial demonstrated the significant risk reduction of any clinical fracture in women taking denosumab in comparison to only calcium and vitamin D. The Z-FAST trials (Zometa-Femara Adjuvant Synergy Trials) demonstrated that IV bisphosphonates also prevented AI-associated bone loss. This trial analyzed the efficacy of giving zoledronate to patients while starting AI therapy versus waiting to give zoledronate after a bone mineral density decrease to a T -score of <2.0. The delayed treatment resulted in a loss of bone mineral density at the lumbar spine and hip. Oral bisphosphonates, such as risedronate, also demonstrated an increased bone mineral density by 2.2% in patients who started risedronate immediately versus a placebo for 2 years. Women on AIs who develop osteoporosis are at an increased risk of bone fracture and musculoskeletal arthralgias. Recommendations have been made that patients on AIs should be offered biphosphonates and calcium to reduce the incidence of these symptoms.
Risk Factors
There are no consistent predictors for the development of risk factors for AIMSS. Some studies have demonstrated an increased risk for arthralgias and musculoskeletal symptoms in women with a low BMI. Women who were overweight with a BMI of 25–30 were less likely to experience AI-related joint pain.
Another risk factor that has demonstrated discordant information is the use of previous hormone replacement therapy such as tamoxifen. In one study, patients who were previously treated with tamoxifen were less likely to develop AI-related joint pain and stiffness, in comparison to those who had never received tamoxifen. However, in another study, prior use of tamoxifen was related to discontinuation of AIs due to the aromatase-inhibitor-associated arthralgia.
In another study in which patients were treated with a taxane, it was noted that those women were four times more likely to experience joint pain.
A final risk factor that has also been researched has been the relationship between lengths of time since cessation of menstruation to onset of AI-associated arthralgia. Research has shown that the time since a woman’s last menstrual period was inversely related to their report of AI-related arthralgia. This concept supports the theory that estrogen withdrawal plays a role in AIMSS since women have lower estrogen levels after menopause.
Conclusion
In conclusion, AIMSS is very common in women taking an AI as part of their breast cancer treatment. Although the exact cause of AIMSS is not clearly known, there is speculation that estrogen has an important role in the proper function of joints and the reduction in estrogen as part of this treatment can contribute to the development of joint symptomatology in users. The early identification and initiation of treatment can help reduce pain, minimize loss of function, and maximize quality of life. Physiatrists can have a very important role in the assessment and treatment of this disabling condition.
References
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