Aromatase inhibitors (AI's) are the most effective adjuvant anti-hormonal therapy for estrogen receptor positive (ER+) post-menopausal breast cancer patients, with superior disease free survival over tamoxifen. However, approximately half of the women who take this drug will develop significant joint pains, termed Aromatase Inhibitor-Induced Arthralgia (AIA). Though this medicine should be taken for 5 years, the joint pain can be so troublesome that 13-20% may prematurely discontinue it because of the arthralgia, thus sacrificing their best chance of disease free survival. Furthermore, daily quality of life is significantly affected by this chronic pain while taking AI therapy. Nonetheless, neither the etiology nor the treatment of AIA is well-understood within the medical community.

It is known that low estrogen levels, as seen on AI therapy, decrease the amount of available, active vitamin D. Low Vitamin D is implicated in non-specific musculoskeletal pain in non-cancer patients, possibly mediated by higher levels of inflammatory cytokines IL-6 and TNF-alpha in a low vitamin D state. Vitamin D replacement has been shown to be helpful for AIA in some small clinical trials. We therefore propose to test the hypothesis that AIA can be effectively prevented by high dose Vitamin D supplementation, and that effective prophylaxis of the problem will lead to improved compliance with AI therapy.

In this clinical trial, we will enroll 184 women who are beginning adjuvant AI therapy and randomize half of them to receive high dose vitamin D (50,000 IU Vitamin D3 per week for 12 weeks, followed by 2000 IU Vitamin D3 daily for 40 weeks), and the other half to receive standard dose vitamin D (800 IU Vitamin D3 daily for 52 weeks). We will assess each woman's baseline joint pains via a questionnaire (Health Assessment Questionnaire-II). We hypothesize that AIA can be effectively prevented with high dose vitamin D, and this will correlate to increased compliance in the high dose vitamin D arm.. The primary endpoint is development of AIA as measured by a defined change in HAQ-II score between baseline and 12 wks. This randomized Phase 2 study is powered to detect an improvement from an expected 33% incidence of AIA in the standard dose group to 18% or less in the high-dose group (alpha=10%, one-tailed). Finally, as an exploratory objective, we will determine whether those in the standard dose vitamin D arm have a correlation between higher levels of inflammatory cytokines and development of AIA.

This study targets a very common cause of pain among breast cancer survivors and aims to offer an effective treatment strategy to alleviate pain and improve quality of life as well as medication compliance.

Citation Format: Polly A. Niravath, Sue Hilsenbeck, Tao Wang, Mothaffar Rimawi. A randomized, controlled trial of high dose vs. standard dose vitamin D for aromatase inhibitor-induced arthralgia in breast cancer survivors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT319. doi:10.1158/1538-7445.AM2014-CT319