Originally published as JCO Early Release 10.1200/JCO.2009.23.3270 on September 14 2009

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Aromatase Inhibitor–Associated Arthralgias

Department of Medicine, Los Angeles BioMedical Research Institute at Harbor UCLA Medical Center, Torrance, CA

The aromatase inhibitors (AIs) have become an established component of adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer.^1–3 Although adherence to AI regimens in clinical trials has been favorable,⁴ in clinical practice the arthralgias associated with AI use adversely influence adherence.^5–7 In this issue of Journal of Clinical Oncology, Sestak et al⁸ and Dizdar et al⁹ provide prospective information on a related adverse effect, AI-associated carpal tunnel syndrome (CTS).

In the ‘Arimidex,’ Tamoxifen, Alone or in Combination (ATAC) breast cancer adjuvant trial comparing tamoxifen to anastrozole, Sestak et al⁸ showed that clinical CTS was reported as an adverse effect more frequently in the anastrozole group compared with the tamoxifen group (2.6% v 0.7%; P < .0001). The syndrome was more common in women less than 60 years old and in those with prior hormone therapy or chemotherapy. Most CTS patients required no intervention, with surgery performed for 11 women (of 3,092) in the anastrozole and two (of 3,094) in the tamoxifen group. These findings are comparable to those from the Intergroup Exemestane Study (IES) breast cancer adjuvant trial, in which surgery for CTS was more common in the exemestane group compared with the tamoxifen group (2.8% v 0.4%; P < .001).¹⁰

Because CTS commonly includes a compression neuropathy of the median nerve at the wrist, thickening of tendons sharing this tunnel represents one etiologic factor.¹¹ The article by Dizdar et al⁹ expands the concept of CTS in AI users in a prospective study of postmenopausal women with early-stage breast cancer. Women receiving AIs and a control population not receiving hormone therapy underwent musculoskeletal sonography and electromyography. As expected, 33% of women taking AIs reported increased arthralgias. Of those who underwent sonography, the tendons of women taking AIs were thicker than those of controls (P < .001), and wrist effusions were more commonly seen in women taking AIs with arthralgias (50%) compared to women either taking AIs without arthralgias (25%) or women not taking AIs (37%; P = .037 for difference between all women taking AIs v controls). Nerve conduction studies were performed in 89 participants who had a diagnosis of CTS made by electromyographic rather than by clinical findings. Women taking AIs with arthralgias more commonly had findings of CTS (46%) compared with women taking AIs without arthralgia (20%) or controls (30%). These findings are supported by a previous report of AI-associated increase in tenosynovial changes shown on magnetic resonance imaging as well as an associated decrease in grip strength.^12,13 If correlation between findings on magnetic resonance imaging, sonography, and electromyography can be established with clinical findings, an opportunity for using these more sensitive tests as intermediate end points in clinical efficacy trials will become available.

How do these current findings on AI-associated CTS relate to available information on AI-associated arthralgias, and what are the implications for clinical practice?^14,15 Arthralgias represent a substantial problem in postmenopausal women even without a breast cancer diagnosis. Information on arthralgia frequency collected in breast cancer trials as a reported adverse effect likely substantially underestimates the magnitude of the problem. In the Women's Health Initiative clinical trials involving postmenopausal women of comparable age to that seen in adjuvant breast cancer trials, arthralgias were prospectively addressed with two questions: Do you have joint pain? (yes/no; is it mild, moderate, or severe), and Do you have joint swelling? (yes/no; is it mild, moderate, or severe). When asked in this fashion, 74% of postmenopausal women without breast cancer reported joint pain, and 34% reported joint swelling.¹⁶ In clinical practice, serial recording of this information can provide a simple quantitative assessment of the arthralgia disease course.

Perhaps the best information on the clinical course and associated risk factors for AI-associated arthralgias comes from the ATAC trial. Women who were obese, those with hormone-receptor–positive breast cancers, and those who had received prior chemotherapy were at significantly increased risk of AI-associated arthralgia.¹⁷ In approximately one third of women, joint symptoms improved, usually within 6 months, in the face of continued therapy.¹⁸ Information regarding this potentially favorable time course should be transmitted to patients as an adherence aid. Similarly, the recent evidence that AI-associated arthralgias may identify patients with a substantially more favorable prognosis¹⁹ can provide further patient incentive to continue therapy.

There does not appear to be a difference in joint symptom problems among the three AIs used in the adjuvant trial setting. The increase in arthralgia frequency above that seen with tamoxifen is between 6% and 7% in the largest trials evaluating anastrozole, letrozole, or exemestane.^10,20,21 Studies evaluating the influence of switching between hormonal regimens found that more than half of women who experienced joint symptoms when taking one AI had fewer symptoms when taking a second AI, regardless of sequence (anastrozole to letrozole or vice versa).^7,22 Although such results could well represent the same duration effect seen in the ATAC trial, they nonetheless represent a potential clinical strategy to enhance adherence to an adjuvant regimen incorporating AI use.

Although their exact etiology is unknown, AI-associated arthralgias are likely related, at least in some degree, to estrogen deprivation, given estrogen's role in collagen maintenance and modulation of pain perception.^{13,16,23–25} The findings from the current report from Dizdar et al⁹ that inflammatory markers did not differ in women with or without arthralgias support prior reports that autoimmune serology does not play a role in the etiology of AI-associated arthralgias.²⁶

Few interventions addressing AI-associated arthralgias have been evaluated in clinical trials. One small pilot effort suggested benefit from a 6-week acupuncture regimen.²⁷

Perhaps the most controversial area regarding AI-associated arthralgias is the role of vitamin D. To support bone health, vitamin D is recommended in conventional dosage of 400 to 800 U/d plus calcium (1,000 mg/d) for women taking AIs.²⁸ However, no definitive role for vitamin D deficiency in AI-associated arthralgias has been established. Although some studies have associated low 25-hydroxyvitamin D (25-OHD) levels (as a measure of vitamin D status) with higher frequency of AI-associated musculoskeletal symptoms, others have not.^26,29–32 In the International Breast Intervention Study 2 (IBIS-2) breast cancer prevention trial comparing anastrozole to placebo, although 83% of evaluated participants (n = 225) had 25-OHD levels of less than 30 ng/mL and could be considered "deficient," baseline 25-OHD levels were not associated with arthralgia increase at 12 months. In addition, anastrozole use led to a small but significant increase in 25-OHD levels after 12 months.³²

Two prospective randomized clinical trials have evaluated vitamin D supplementation on joint symptoms in cancer-free populations. The Women's Health Initiative randomly assigned 36,282 postmenopausal women to daily calcium carbonate (1,000 mg) plus vitamin D3 (400 U) or placebo.³³ Joint symptom change was evaluated in a 6% subgroup (n = 1,911) assessed at baseline and after 2 years follow-up. Although joint pain was reported by 73% of participants at entry, joint symptoms 2 years after randomization did not differ between the vitamin D supplement and placebo groups.¹⁶ In a second trial, 50 individuals with diffuse musculoskeletal pain who had 25-OHD levels less than 20 ng/mL (approximately 50 nm/L) were randomly assigned to receive placebo or high-dose vitamin D2 (50,000 U/wk) for 3 months. Again, vitamin D supplementation had no effect on musculoskeletal pain.³⁴ Nonetheless, the question is considered open, as two ongoing studies are evaluating high-dose vitamin D3 for AI-associated arthralgias.^35,36 These efforts received some support from a prospective single-arm study of 50 breast cancer patients beginning letrozole who received vitamin D3, 50,000 U/wk for 12 weeks. Although not statistically significant, some clinical relief of joint pain was seen in 23% of participants.³⁷

The available evidence regarding a potential role for vitamin D in mitigating AI-associated arthralgias should be cautiously interpreted by clinicians in practice. Even relatively low vitamin D supplementation doses of less than 1,000 U/d have been associated with significantly increased gastrointestinal symptoms (risk ratio [RR] = 1.04; 95% CI, 1.00 to 1.08), increased hypercalcemia (RR = 2.35; 95% CI, 1.59 to 3.47), and increased renal disease (RR = 1.16; 95% CI, 1.02 to 1.33).³⁸ In addition, no long-term safety information on high-dose vitamin D administration is available. Clinicians are advised to await results from the ongoing clinical trials before implementing diagnostic and therapeutic intervention strategies that target 25-OHD levels.

An optimal management strategy for AI-associated arthralgias has not been identified. However, a recent expert panel addressed available evidence and developed an algorithm suggesting a treatment plan for this condition, largely based on strategies used successfully for peripheral joint pain management in other conditions.^15,39,40 Use of high-dose nonsteroidal anti-inflammatory drugs or selective COX-2 inhibitors as initial short-term therapy were recommended to address initial pain relief, with subsequent titration to minimum effective dosage. With recommended high starting dosages (ibuprofen 1,600-2,400 mg daily, naproxen 1,000 mg daily, and celecoxib 400 mg daily), such strategies require familiarity with adverse effects of these agents and contraindications to their use and, preferably, referral to specialists in managing joint pain.¹⁵

In a review of 856 patients with nonmetastatic breast cancer seen in one institution, information on bone mineral density, arthralgia, generalized bone pain or myalgia, and bone fracture were evaluated after patients began either an AI or tamoxifen, and use of calcium and bisphosphonates were recorded. A significant association between greater joint symptoms with lower bone mineral density was seen (P < .001), with women receiving an AI plus calcium and bisphosphonate having fewer musculoskeletal symptoms and fractures. The authors concluded that women receiving AIs who developed osteoporosis are at increased risk of musculoskeletal symptoms and that concurrent use of calcium and bisphosphonate may reduce the likelihood of these symptoms.⁴¹ Given the current interest in bisphosphonate use as adjuvant breast cancer therapy for bone loss and potentially for recurrence risk reduction, a prospective trial evaluating the safety and efficacy of combined short-term, high-dose anti-inflammatory drug use and ongoing bisphosphonates for AI-associated arthralgias seems reasonable.⁴²

Although AI-associated arthralgias represent a substantial problem, most women are able to continue their AI treatment regimen. Further research regarding the etiology, risk factors, and improved interventions is clearly needed. At present, oncologists should carefully observe their patients for development of this problem, clearly express to their patients the benefits of continued adherence, and provide the limited available therapies.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Rowan T. Chlebowski, AstraZeneca (C), Novartis (C), Pfizer (C) Stock Ownership: None Honoraria: Rowan T. Chlebowski, AstraZeneca, Novartis Research Funding: None Expert Testimony: None Other Remuneration: None

NOTES

See accompanying articles on pages 4955 and 4961

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