Arthritis and Arthralgia Caused by Aromatase Inhibitors

Jacob Schor ND FABNO

October 17, 2008

Aromatase inhibitors have become the standard of care for hormonal treatment of post-menopausal breast cancer.  The consensus among researchers is that these new drugs are safer than the older drug tamoxifen that they are replacing.  Thought they pose less danger of serious injury, they do create more complaints from symptomatic side effects.

The most significant complaint that our patients complain of is joint pain.  It is as if they have suddenly developed arthritis after starting the drug.  The simple explanation for these symptoms is that estrogen keeps the body moist inside and that without estrogen, everything dries up, including the joints.  Without lubrication the joints get irritated and then swollen.

This condition is now being classified into two general categories, joint pain as in arthritis and a more generalized discomfort involving muscle and skeleton, what the journals are calling aromatase inhibitor arthralgia. Either can be so severe that patients will discontinue taking the prescribed regimen of treatment.

The other problem with these new drugs is that unlike estrogen or tamoxifen they do not stimulate the bone to grow.  Bone loss is accelerated and osteoporosis becomes a significant risk. That being the case, the recommendation is that, “All patients initiating AI therapy should receive calcium and vitamin D supplements.” Greater attention is now being directed at these patients to prevent bone loss.   Yet it is unclear that maintaining bone density prevents either the arthritis or arthralgia.

It wasn’t until last month that we had a good idea of how common these symptoms are.  A study that appeared in the September 2008 issue of Lancet Oncology analyzed data from 5,433 women who took part in the ATAC trial that compared women taking tamoxifen or anastrozole.  These women were randomly assigned to take anastrozole or tamoxifen, and at the start of the trial had no joint symptoms.

“In this trial, the major risk factors for developing joint symptoms were previous HRT, hormone-receptor positivity, previous chemotherapy, obesity, and treatment with anastrozole.”

Analyzing this data revealed some interesting trends.  Having used hormone replacement therapy (HRT) at some point earlier in life increased the chance of a woman having problems taking the aromatase inhibitor.  About 41% of the women who had used HRT developed joint symptoms compared to only 28% who hadn’t.  Women whose breast cancer was hormone receptor negative had fewer joint symptoms compared to the hormone receptor positive tumors,  27% compared to 34%.  Starting treatment with chemotherapy made things a bit worse.  Just under 38% of the women who received chemo as the first part of their treatment developed joint symptoms compared to only 31% who did not have chemo.  Obese women reported slightly more symptoms than non-obese, 37% to 31%.

A 2007 paper in the Journal of Clinical Oncology reported that in a survey of 200 women “ 94 (47%) reported having AI-related joint pain and 88 (44%) reported AI-related joint stiffness.”  

The Lancet study was looking at women who had no pain to begin with.  Women who are in pain at the onset of treatment with aromatase inhibitors may find their symptoms worsen. A paper early in 2008 in the journal Praxis describes an aggravation of symptoms caused by an aromatase inhibitor in a patient suffering from chronic pain.

What’s going on that causes these symptoms?  Though the dry joint analogy works for most patients, biology is not so simple.  An article in the July 2008 issue of the Journal of Clinical Oncology started to investigate this.  The authors compared MRIs of the wrists and hands of breast cancer patients taking either aromatase inhibitors or tamoxifen. After six months there were clear changes visible on the scans that correlated with significant decreases in grip strength.   OK that probably doesn’t come as a surprise to anyone having these problems. 

These symptoms are resistant to therapy.  Steroids and NSAIDs provide little relief.  Same story with all those supplements and other stuff we routinely suggest for these kinds of symptoms, not much helps except discontinuing the drug.  Even then it can take  awhile until the joints heal.  In some patients it doesn’t appear that they ever do completely.  There have been several recent publications that suggest some possibility of relief. 

The first is a pilot study performed at Columbia University in New York that used acupuncture to treat joint problems associated with AIs. Patients involved in the study reported a reduction in pain and less interference in daily activity.  But joint pain is a hard thing to study and arthritis research is infamous for having strong placebo effects.

There is  mention of using high dose vitamin D but I still need to track down details.

The most intriguing paper was published the first week of September in Medical Hypotheses and suggests that excess melatonin may play a role in these symptoms.  The author, Ron Burk, points out two things.  First, that similar symptoms occur with any estrogen depleting therapy and second, there is a circadian pattern to the discomfort.  Typically the discomfort is worse in the morning.  Most would explain that this is due to lack of motion at night and a build up of joint fluid. 

 

Burk points out that back in the early 1990s a number of reports were published describing ‘postchemotherapy rheumatism.’  The first appears to be Loprinzi  from the Mayo Clinic in  April of 1993.   Once named, other reports on the condition showed up; Smith in August 1993, Siegel and Michl in October 1993 , and so on.  The most telling was a survey published in 1999 that looked at 111 women who had been treated for breast cancer.  Over two years after treatment, “41% of the BC group reported that current rheumatoid symptoms exceeded those experienced prior to diagnosis.” Thus it might be the chemo that caused the problems or the lack of estrogen that resulted from chemo induced menopause or the tamoxifen many of them were taking.

Still Burk suggests there may be other things at work. 

Burk suggests, “that estrogen depletion can increase pineal melatonin, that the ability of light to suppress pineal melatonin is more variable than once thought, and that an altered melatonin cycle is associated with rheumatoid arthritis patients, where identical circadian symptoms present. It is hypothesized that when AIs decrease estrogen levels, light-induced melatonin suppression (LIMS) loses efficacy, leading to an abnormal melatonin cycle as seen in rheumatoid arthritis patients, producing (via mechanisms not yet understood) the symptoms of morning stiffness.”

These details may be more than even those of you suffering from these problems need to know.  I assume everyone else stopped reading several paragraphs back.  If you would like to read Burk’s entire paper, let me know.  I’ll send you a copy.

The bottom line is that Burk suggests that suppressing melatonin production during the daytime by exposure to either sunlight or bright lights will reduce the pain in women taking aromatase inhibitors.  He suggests either daytime out door light exposure or exposure to artificial lights designed to suppress melatonin production.  “This hypothesis predicts that some patients can suppress the circadian joint pain associated with aromatase inhibitors merely by getting sufficient hours of daily retinal sunlight.” 

He reports on a patient whose symptoms were relieved by spending lots of time outside.  The benefit was duplicated by having the patient wear a hat with light emitting diodes shinning in her face duplicating the melatonin suppressive effect of daylight.

A report of one patient benefiting from a ‘new treatment’ is not proof of anything.  Still when we have little to offer in the way of effective treatments, trying something that doesn’t cost money and poses no risk seems worth a try.  Well, costing little money might be an exaggeration.  Burk’s patient first noticed symptom improvement while on vacation.  A week on a Mexican beach will cost something.  Given that many patients discontinue taking aromatase inhibitors because of the pain they cause and these drugs are apparently effective at reducing risk of cancer recurrence, the vacation may be a small price to pay.

If you can’t afford or don’t have the time to go on vacation consider the high intensity blue lights that we have written about in the past. 

http://denvernaturopathic.com/bluelightandmelatonin.htm

 

 

Med Hypotheses. 2008 Sep 7.

Aromatase inhibitor-induced joint pain: Melatonin's role.

Burk R.

    Burk Labs, 9414 168th Place NE, Redmond, WA 98052, USA.

    Aromatase inhibitors (AIs) enjoy increasing use in breast cancer adjuvant therapy. But the joint pain associated with AIs significantly reduces patient adherence despite the clear survival benefits of this class of drugs. Two clues point to a novel hypothesis for this unexplained symptom. First, realizing that joint pain is associated with virtually all estrogen-depleting breast cancer treatments suggests that the cause is broader than this particular class of drugs. Second, the strongly circadian nature of these symptoms suggests circadian hormone involvement. This puts new light on some existing research findings: that estrogen depletion can increase pineal melatonin, that the ability of light to suppress pineal melatonin is more variable than once thought, and that an altered melatonin cycle is associated with rheumatoid arthritis patients, where identical circadian symptoms present. It is hypothesized that when AIs decrease estrogen levels, light-induced melatonin suppression (LIMS) loses efficacy, leading to an abnormal melatonin cycle as seen in rheumatoid arthritis patients, producing (via mechanisms not yet understood) the symptoms of morning stiffness. Not all frequencies of retinal light are equally effective at suppressing pineal melatonin; most artificial lighting has less relevant spectral density than sunlight. This hypothesis predicts that some patients can suppress the circadian joint pain associated with aromatase inhibitors merely by getting sufficient hours of daily retinal sunlight. A single patient history is discussed, in which a series of treatments had no effect on AI joint pain, while extended exposure to sunlight produced a definitive elimination of symptoms the next morning. To conclusively demonstrate the role of melatonin, light-emitting diodes of an appropriate frequency were mounted on a cap for the patient to wear. If worn first thing in the morning, the cap sharply curtailed the duration of morning stiffness. If worn for a sufficient number of hours during the day, the cap suppressed symptoms the next morning, just as sunlight did. Because of evidence for melatonin's oncostatic properties, this hypothesis potentially has implications beyond decreasing the number of patients that discontinue AIs. It may be that some portion of the survival benefit of AIs is due to their indirect effect on melatonin, not just their direct effect on estrogen.

J Cancer Surviv. 2007 Dec;1(4):283-91.

    Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients.

    Crew KD, Capodice JL, Greenlee H, Apollo A, Jacobson JS, Raptis G, Blozie K, Sierra A, Hershman DL.

    Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

    INTRODUCTION: Aromatase inhibitors (AIs) have become the standard of care for the adjuvant treatment of postmenopausal, hormone-sensitive breast cancer. However, patients receiving AIs may experience joint symptoms, which may lead to early discontinuation of this effective therapy. We hypothesize that acupuncture is a safe and effective treatment for AI-induced arthralgias. METHODS: Postmenopausal women with early-stage breast cancer who had self-reported musculoskeletal pain related to adjuvant AI therapy were randomized in a crossover study to receive acupuncture twice weekly for 6 weeks followed by observation or vice-versa. The intervention included full body and auricular acupuncture, and a joint-specific point prescription. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life measure, and serum levels of inflammatory markers, IL-1 beta and TNF-alpha. RESULTS: Twenty-one women were enrolled and two discontinued early. From baseline to the end of treatment, patients reported improvement in the mean BPI-SF worst pain scores (5.3 to 3.3, p = 0.01), pain severity (3.7 to 2.5, p = 0.02), and pain-related functional interference (3.1 to 1.7, p = 0.02), as well as the WOMAC function subscale and FACT-G physical well-being (p = 0.02 and 0.04, respectively). No adverse events were reported. DISCUSSION/CONCLUSIONS: In this pilot study, acupuncture reduced AI-related joint symptoms and improved functional ability and was well-tolerated. IMPLICATIONS FOR CANCER SURVIVORS: Musculoskeletal side effects are common among breast cancer survivors on adjuvant AI therapy, therefore, effective treatments are needed for symptom relief and to improve adherence to these life-saving medications.

Aromatase inhibitor-associated arthralgia syndrome.

Harold J. Burstein.

The Breast 16.3 (June 2007): p223(12).

To link to full-text access for this article, visit this link: http://dx.doi.org.ezproxy.denverlibrary.org:2048/10.1016/j.breast.2007.01.011

Aromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. Clinical trials have assessed 5 years of AI therapy, either as an alternative to tamoxifen for primary adjuvant therapy of breast cancer, or after 5 years of adjuvant tamoxifen. Treatment of 2-3 years' duration after 2-3 years of tamoxifen has also been studied. AI therapy brings side effects related to estrogen deprivation, and this side effect profile differs in clinically relevant ways from that seen with tamoxifen. In particular, the selective estrogen receptor modulatory effects of tamoxifen contribute to menopausal symptoms, vaginal discharge, and the rare but worrisome risks of thromboembolism and uterine carcinoma. By contrast, the low levels of estrogen achieved with aromatase inhibition contribute to menopausal symptoms, vaginal dryness and sexual dysfunction, and accelerated bone demineralization with risk of osteoporosis and osteoporotic fracture. Clinical experience also suggests that AI therapy is associated with a novel musculoskeletal side effect consisting of an arthralgia syndrome. The actual incidence of AI-associated arthralgias or musculoskeletal symptoms is not known, though such symptoms are quite prevalent and appear more commonly with AI use than with tamoxifen. Arthralgias can be a reason for discontinuation of AI treatment. The possible mechanisms of AI-associated arthralgia are unclear. Estrogen deficiency causes bone loss, which in turn contributes to arthralgia. Less well-studied functions of estrogen include regulating immune cells and cytokines involved in bone remodeling, and modulating pain sensitivity at the level of the central nervous system. Arthralgia and arthritis have seldom been rigorously differentiated in clinical trials of AIs. Assessment of inflammatory and rheumatologic markers, as well as detailed evaluation of patient symptoms using appropriate quality-of-life instruments, may be warranted in order to understand both the symptoms and the etiology of the arthralgia syndrome. Treatment options for arthralgia (primarily non-steroidal anti-inflammatory drugs) are currently inadequate, but areas of active research include high-dose vitamin D and new-targeted therapies to inhibit bone loss.

Breast Cancer Res Treat. 2008 May;109(2):403. Epub 2007 Jul 11.

    Vitamin D intake may be a predictor of response to aromatase inhibitors in postmenopausal women with hormone receptor positive breast cancer.

    Dizdar O, Bulut N, Altundag K.

 

Ther Clin Risk Manag. 2008 Feb;4(1):189-204.

    Long-term safety of aromatase inhibitors in the treatment of breast cancer.

    Nabholtz JM.

    Breast Cancer Research Institute La Prandie, Valojoulx, France.

    Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI), anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects) or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction) class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.

Breast. 2007 Jun;16(3):223-34. Epub 2007 Mar 21.

    Aromatase inhibitor-associated arthralgia syndrome.

    Burstein HJ.

    Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. hburstein@partners.org <hburstein@partners.org>

    Aromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. Clinical trials have assessed 5 years of AI therapy, either as an alternative to tamoxifen for primary adjuvant therapy of breast cancer, or after 5 years of adjuvant tamoxifen. Treatment of 2-3 years' duration after 2-3 years of tamoxifen has also been studied. AI therapy brings side effects related to estrogen deprivation, and this side effect profile differs in clinically relevant ways from that seen with tamoxifen. In particular, the selective estrogen receptor modulatory effects of tamoxifen contribute to menopausal symptoms, vaginal discharge, and the rare but worrisome risks of thromboembolism and uterine carcinoma. By contrast, the low levels of estrogen achieved with aromatase inhibition contribute to menopausal symptoms, vaginal dryness and sexual dysfunction, and accelerated bone demineralization with risk of osteoporosis and osteoporotic fracture. Clinical experience also suggests that AI therapy is associated with a novel musculoskeletal side effect consisting of an arthralgia syndrome. The actual incidence of AI-associated arthralgias or musculoskeletal symptoms is not known, though such symptoms are quite prevalent and appear more commonly with AI use than with tamoxifen. Arthralgias can be a reason for discontinuation of AI treatment. The possible mechanisms of AI-associated arthralgia are unclear. Estrogen deficiency causes bone loss, which in turn contributes to arthralgia. Less well-studied functions of estrogen include regulating immune cells and cytokines involved in bone remodeling, and modulating pain sensitivity at the level of the central nervous system. Arthralgia and arthritis have seldom been rigorously differentiated in clinical trials of AIs. Assessment of inflammatory and rheumatologic markers, as well as detailed evaluation of patient symptoms using appropriate quality-of-life instruments, may be warranted in order to understand both the symptoms and the etiology of the arthralgia syndrome. Treatment options for arthralgia (primarily non-steroidal anti-inflammatory drugs) are currently inadequate, but areas of active research include high-dose vitamin D and new-targeted therapies to inhibit bone loss.

 

Ann Oncol. 2008 Aug;19(8):1407-16. Epub 2008 Apr 29.Click here to read Links

    Practical guidance for the management of aromatase inhibitor-associated bone loss.

    Hadji P, Body JJ, Aapro MS, Brufsky A, Coleman RE, Guise T, Lipton A, Tubiana-Hulin M.

    Department of Gynecology, Philipps-University of Marburg, Marburg, Germany.

    BACKGROUND: Recent studies indicate that women with breast cancer are at increased risk of fracture compared with their age-matched peers. Current treatment guidelines are inadequate for averting fractures in osteopenic women, especially those receiving aromatase inhibitor (AI) therapy. Therefore, we sought to identify clinically relevant risk factors for fracture that can be used to assess overall fracture risk and to provide practical guidance for preventing and treating bone loss in women with breast cancer receiving AI therapy. METHODS: Systematic review of pertinent information from published literature and meeting abstracts through December 2007 was carried out to identify factors contributing to fracture risk in women with breast cancer. An evidence-based medicine approach was used to select risk factors that can be used to determine when to initiate bisphosphonate treatment of aromatase inhibitor-associated bone loss (AIBL). RESULTS: Fracture risk factors were chosen from large, well-designed, controlled, population-based trials in postmenopausal women. Evidence from multiple prospective clinical trials in women with breast cancer was used to validate AI therapy as a fracture risk factor. Overall, eight fracture risk factors were validated in women with breast cancer: AI therapy, T-score <-1.5, age >65 years, low body mass index (BMI <20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking. Treatment recommendations were derived from randomized clinical trials. CONCLUSIONS: The authors recommend the following for preventing and treating AIBL in women with breast cancer. All patients initiating AI therapy should receive calcium and vitamin D supplements. Any patient initiating or receiving AI therapy with a T-score >/=-2.0 and no additional risk factors should be monitored every 1-2 years for change in risk status and bone mineral density (BMD). Any patient initiating or receiving AI therapy with a T-score <-2.0 should receive bisphosphonate therapy. Any patient initiating or receiving AI therapy with any two of the following risk factors-T-score <-1.5, age >65 years, low BMI (<20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking-should receive bisphosphonate therapy. BMD should be monitored every 2 years, and treatment should continue for at least 2 years and possibly for as long as AI therapy is continued. To date, the overwhelming majority of clinical evidence supports zoledronic acid 4 mg every 6 months to prevent bone loss in women at high risk. Although there is a trend towards fewer fractures with zoledronic acid, studies completed to date have not been designed to capture significant differences in fracture rate, and longer follow-up is needed.

 

Cancer Treat Rev. 2008;34 Suppl 1:S31-42. Epub 2008 May 16.

    Bone loss in patients with breast cancer receiving aromatase inhibitors and associated treatment strategies.

    Coleman RE, Body JJ, Gralow JR, Lipton A.

    Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, United Kingdom. r.e.coleman@sheffield.ac.uk

    Hormone-receptor-positive breast cancer in postmenopausal women is treated increasingly with aromatase inhibitors because of increased efficacy and reduced incidence of endometrial cancer compared with tamoxifen. However, aromatase inhibitor therapy increases bone turnover as a result of nearly complete oestrogen depletion, leading to increases in bone loss and fragility fractures that erode patients' functional independence and quality of life. Management of patients with aromatase inhibitor-associated bone loss (AIBL) is currently evolving and intervention strategies are under investigation. Although no treatments are specifically approved for AIBL, bisphosphonates are currently the intervention of choice for patients with low bone mineral density or evidence of rapid bone turnover, along with adequate calcium and vitamin D supplementation and a healthy lifestyle. In this setting, the majority of information available regarding bisphosphonate efficacy is from studies of intravenous zoledronic acid (4 mg) every 6 months. Data from four large international studies (three of identical design in postmenopausal women and one in premenopausal women) indicate that zoledronic acid is effective in the management of AIBL. Treatment algorithms based on risk factors and bone mineral density are under development, and the results of ongoing studies should help define optimal bone health management for patients undergoing aromatase inhibitor treatment for early breast cancer.

 

Lancet Oncol. 2008 Sep;9(9):866-72. Epub 2008 Aug 12.

     Comment in:

        Lancet Oncol. 2008 Sep;9(9):817-8.

    Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis.

    Sestak I, Cuzick J, Sapunar F, Eastell R, Forbes JF, Bianco AR, Buzdar AU; ATAC Trialists' Group.

    Cancer Research UK, Centre for Epidemiology, Mathematics, and Statistics, Wolfson Institute of Preventive Medicine, London, UK.

    BACKGROUND: Joint symptoms (eg, arthralgia and arthritis) are a well-known side-effect of aromatase inhibitors. Low oestrogen concentrations and postmenopausal status are associated with the development of these symptoms. Chemotherapy can also induce joint symptoms, but tamoxifen seems to have little effect on their incidence. The aim of this study was to assess the relative importance of different risk factors for treatment-emergent joint symptoms in patients assigned to anastrozole or tamoxifen as adjuvant treatment for postmenopausal breast cancer. METHODS: The Arimidex Tamoxifen Alone or in Combination (ATAC) trial randomly assigned 9366 postmenopausal women to anastrozole (1 mg/day), to tamoxifen (20 mg/day), or to a combination of both. Our analyses were based on data from case reports of 5433 women who were randomly assigned to anastrozole or tamoxifen, who started with their allocated treatment, and who did not have joint symptoms at entry (anastrozole group: n=2698; tamoxifen group: n=2735). The analysis was restricted to the occurrence of joint symptoms at any time during active treatment or within 14 days of its discontinuation. Joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder on a case-report form. Joint disorders were defined as reports of cervical spondylosis, osteoarthritis, and disc herniation. The date of occurrence was recorded, along with a severity score (ie, mild, moderate, or severe). Our analyses were done by use of logistic regression. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. FINDINGS: 777 of 1914 women (40.6%) who used hormone replacement therapy (HRT) before trial entry developed joint symptoms compared with 1001 of 3519 women (28.4%) without previous HRT use (odds ratio [OR] 1.72 [95% CI 1.53-1.93]). Women with hormone-receptor-negative breast cancer developed significantly fewer joint symptoms compared with those with hormone-receptor-positive tumours (124 of 461 [26.9%] vs 1556 of 4548 [34.2%]; OR 0.71 [0.57-0.88]). Women for whom chemotherapy was part of their initial treatment developed significantly more joint symptoms than those who did not receive it (461 of 1219 women [37.8%] vs 1317 of 4214 women [31.3%]; OR 1.34 [1.17-1.53]). Obese women (body-mass index [BMI] >30 kg/m(2)) reported more joint symptoms than women with a BMI of 25-30 kg/m(2) or those with a BMI <25 kg/m(2) (504 of 1354 women [37.2%] vs 502 of 1926 women [31.3%; OR 1.01 (0.88-1.16)] vs 592 of 1908 women [31.0%; OR 1.32 (1.14-1.53)]) and women on anastrozole reported more joint symptoms compared with those on tamoxifen (949 of 2698 women [35.2%] vs 829 of 2735 women [30.3%]; OR 1.25 [1.11-1.40]). All significant risk factors from the univariate analysis were included in a multivariate analysis and remained significant with little change. INTERPRETATION: In this trial, the major risk factors for developing joint symptoms were previous HRT, hormone-receptor positivity, previous chemotherapy, obesity, and treatment with anastrozole. Discussion of identified risk factors is appropriate when counselling women before initiation of adjuvant hormonal treatment.

 

J Clin Oncol. 2007 Sep 1;25(25):3877-83.

    Comment in:

        J Clin Oncol. 2007 Sep 1;25(25):3797-9.

    Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer.

    Crew KD, Greenlee H, Capodice J, Raptis G, Brafman L, Fuentes D, Sierra A, Hershman DL.

    Department of Medicine and the Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

    PURPOSE: Aromatase inhibitors (AIs) improve survival in postmenopausal women with hormone-sensitive breast cancer, but can cause joint pain and stiffness. The purpose of the current study was to evaluate the prevalence of and identify risk factors for AI-related joint symptoms. PATIENTS AND METHODS: We performed a cross-sectional survey of consecutive postmenopausal women receiving adjuvant AI therapy for early-stage hormone-sensitive breast cancer at an urban academic breast oncology clinic. Patients completed a 25-item self-administered questionnaire assessing the presence of joint symptoms that started or worsened after initiating AIs. Multivariate regression was used to compare those with AI-related arthralgia with those who did not report symptoms, adjusting for demographic and clinical factors. RESULTS: Of 200 patients who completed the survey, 94 (47%) reported having AI-related joint pain and 88 (44%) reported AI-related joint stiffness. In multiple logistic regression analysis, being overweight (body mass index of 25 to 30 kg/m(2)) and prior tamoxifen therapy were inversely associated with AI-related joint symptoms. Patients who received taxane chemotherapy were more than four times more likely than other patients to have AI-related joint pain and stiffness (odds ratio [OR] = 4.08, 95% CI, 1.58 to 10.57 and OR = 4.76; 95% CI, 1.84 to 12.28, respectively). CONCLUSION: Our study suggests that AI-related joint symptoms are more prevalent than what has been described previously in clinical trials. The success of AI therapy depends on patients' ability to adhere to treatment recommendations; therefore, additional studies of interventions that may alleviate these symptoms are needed.

Praxis (Bern 1994). 2008 Feb 6;97(3):137-41.Links

    [Intensification of a diffuse chronic pain syndrome by the introduction of an aromatase inhibitor]

    [Article in French]

    Nemitz N, Kurmann PT, Van Linthoudt D.

    Département de Médecine, service de Rhumatologie, Hôpital Neuchâtelois, La Chaux-de-Fonds.

    A case of a menopausal woman known for a chronic diffuse pain syndrome and breast cancer positive for estrogen receptors is presented. She developed an increase of her diffuse pain syndrome and joint aches after the introduction of an aromatase inhibitor. Soreness quickly improved after the interruption of the drug. We emphasize some etiological hypotheses concerning the painful symptoms, especially the role of aromatase and estrogens.

 

J Clin Oncol. 2008 Jul 1;26(19):3147-52. Epub 2008 May 12.Click here to read Links

    Comment in:

        J Clin Oncol. 2008 Jul 1;26(19):3120-1.

    Prospective study to assess short-term intra-articular and tenosynovial changes in the aromatase inhibitor-associated arthralgia syndrome.

    Morales L, Pans S, Verschueren K, Van Calster B, Paridaens R, Westhovens R, Timmerman D, De Smet L, Vergote I, Christiaens MR, Neven P.

    Department of Obstetrics and Gynecology, Division of Gynecological Oncology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

    PURPOSE: Arthralgia is an adverse class effect of aromatase inhibitors (AIs). To date, its exact mechanism remains unclear. The purpose of this study was to investigate the changes in clinical rheumatologic features and magnetic resonance imaging (MRI) of hands and wrists in AI and tamoxifen users. PATIENTS AND METHODS: This is a prospective single-center study including 17 consecutive postmenopausal patients with early breast cancer receiving either tamoxifen (n = 5) or an AI (n = 12). At baseline and after 6 months, patients filled in a rheumatologic history questionnaire and a rheumatologic examination including a grip strength test was done. At the same time points, MRI of both hands and wrists was performed. The primary end point was tenosynovial changes from baseline on MRI. Secondary end points were changes from baseline for morning stiffness, grip strength, and intra-articular fluid on MRI. Wilcoxon signed ranks was used to test changes from baseline and the Spearman correlation coefficient to assess the association between rheumatologic and MRI changes from baseline. RESULTS: At 6 months, patients on AI had a decrease in grip strength (P = .0049) and an increase in tenosynovial changes (P = .0010). The decrease in grip strength correlated well with the tenosynovial changes on MRI (P = .0074). Only minor changes were seen in patients on tamoxifen. AI users reported worsening of morning stiffness and showed an increase in intra-articular fluid on MRI. CONCLUSION: The functional impairment of hands in the AI-associated arthralgia syndrome is characterized by tenosynovial changes on MRI correlating with a significant decrease in hand grip strength.

 

J Cancer Surviv. 2007 Dec;1(4):283-91.

    Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients.

    Crew KD, Capodice JL, Greenlee H, Apollo A, Jacobson JS, Raptis G, Blozie K, Sierra A, Hershman DL.

    Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

    INTRODUCTION: Aromatase inhibitors (AIs) have become the standard of care for the adjuvant treatment of postmenopausal, hormone-sensitive breast cancer. However, patients receiving AIs may experience joint symptoms, which may lead to early discontinuation of this effective therapy. We hypothesize that acupuncture is a safe and effective treatment for AI-induced arthralgias. METHODS: Postmenopausal women with early-stage breast cancer who had self-reported musculoskeletal pain related to adjuvant AI therapy were randomized in a crossover study to receive acupuncture twice weekly for 6 weeks followed by observation or vice-versa. The intervention included full body and auricular acupuncture, and a joint-specific point prescription. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life measure, and serum levels of inflammatory markers, IL-1 beta and TNF-alpha. RESULTS: Twenty-one women were enrolled and two discontinued early. From baseline to the end of treatment, patients reported improvement in the mean BPI-SF worst pain scores (5.3 to 3.3, p = 0.01), pain severity (3.7 to 2.5, p = 0.02), and pain-related functional interference (3.1 to 1.7, p = 0.02), as well as the WOMAC function subscale and FACT-G physical well-being (p = 0.02 and 0.04, respectively). No adverse events were reported. DISCUSSION/CONCLUSIONS: In this pilot study, acupuncture reduced AI-related joint symptoms and improved functional ability and was well-tolerated. IMPLICATIONS FOR CANCER SURVIVORS: Musculoskeletal side effects are common among breast cancer survivors on adjuvant AI therapy, therefore, effective treatments are needed for symptom relief and to improve adherence to these life-saving medications.

 

J Clin Oncol. 1993 Apr;11(4):768-70.Click here to read Links

    Comment in:

        J Clin Oncol. 1993 Aug;11(8):1625-6.

        J Clin Oncol. 1993 Oct;11(10):2051.

        J Clin Oncol. 1993 Oct;11(10):2051-2.

    Postchemotherapy rheumatism.

    Loprinzi CL, Duffy J, Ingle JN.

    Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905.

    PURPOSE: This report describes a previously unreported clinical phenomenon that occurs in some patients after completion of combination chemotherapy. METHODS AND RESULTS: Eight case reports are presented. Affected patients developed a syndrome of myalgias/arthralgias within several months of completing cyclophosphamide/fluorouracil (5FU)-containing adjuvant combination chemotherapy for breast cancer. These symptoms did not appear to be related to cancer recurrence or any common rheumatologic disorder. The syndrome generally resolved over several months. CONCLUSION: Postchemotherapy rheumatism is a syndrome of myalgias/arthralgias that usually develops 1 to 3 months after completion of adjuvant chemotherapy. Recognition of this syndrome can limit the need for extensive work-ups to exclude recurrent breast cancer or inflammatory rheumatologic diseases.

J Clin Oncol. 1993 Aug;11(8):1625-6.

    Comment on:

        J Clin Oncol. 1993 Apr;11(4):768-70.

    Additional cases of postchemotherapy rheumatism.

    Smith DE.

J Clin Oncol. 1993 Oct;11(10):2051.

    Comment on:

        J Clin Oncol. 1993 Apr;11(4):768-70.

    Postchemotherapy rheumatism: is this a menopausal symptom?

    Siegel JE.

J Clin Oncol. 1993 Oct;11(10):2051-2.

    Comment on:

        J Clin Oncol. 1993 Apr;11(4):768-70.

    More postchemotherapy rheumatism.

    Michl I, Zielinski CC.

J Pain Symptom Manage. 1999 Aug;18(2):85-94.

    Rheumatoid symptoms following breast cancer treatment: a controlled comparison.

    Andrykowski MA, Curran SL, Carpenter JS, Studts JL, Cunningham L, McGrath PC, Sloan DA, Kenady DE.

    Department of Behavioral Science, University of Kentucky College of Medicine, Lexington 40536-0086, USA.

    The prevalence of rheumatoid symptoms following breast cancer (BC) treatment was examined. Breast cancer patients (n = 111) who were a mean of 27.6 months postcompletion of BC treatment and 99 otherwise healthy women with benign breast problems (BBP) completed a self-report measure that assessed current joint pain, swelling, and stiffness, as well as measures of quality of life. Results supported a hypothesized link between BC and rheumatoid symptoms: (1) the BC group was more likely to report joint stiffness lasting more than 60 min following morning waking; (2) the prevalence of unilateral or bilateral joint point or swelling was greater (P < 0.10) in the BC group for four of 10 joint-symptom combinations examined, with differences between the BC and BBP groups in upper extremity joint swelling particularly pronounced; and (3) 41% of the BC group reported that current rheumatoid symptoms exceeded those experienced prior to diagnosis. Within the BC group, the data did not support postchemotherapy rheumatism as an explanation for rheumatoid symptoms. Rather, data suggested that symptoms were associated with surgical management of BC. Finally, among women in the BC group with the most severe joint pain, only a minority were receiving medication for these symptoms. Given the relationship between rheumatoid symptoms and quality of life, more systematic research examining potential contributing factors such as menopausal status, concurrent lymphedema, and weight gain is warranted.