Abstract
Purpose
Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment.
Methods
We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled.
Results
The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development.
Conclusion
Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Rimawi M, Osborne C (2010) Adjuvant systemic therapy: endocrine therapy. In: Harris J, Morrow M, Lippman M, Osborne C (eds) Diseases of the breast, 4th edn. Lippincoot Williams & Wilkins, Philadelphia, Pennsylvania, pp 610–630
Mouridsen H, Giobbie-Hurder A, Goldhirsch A (2009) Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 361(8):766–776
Howell A, Cuzick J, Baum M et al (2005) Results of the ATAC trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62
Coombes R, Hall E, Gibson L, Paridaens R, Jassem J, Delozier T et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11):1081–1092
Niravath P (2013) Aromatase inhibitor-induced arthalgia: a review. Ann Oncol 24(6):1443–1449
Boonstra A, van Zadelhoff J, Timmer-Bonte A, Ottevanger P, Beurskens C, van Laarhoven H (2013) Arthralgia during aromatase inhibitor treatment in early breast cancer patients: prevalence, impact, and recognition by healthcare providers. Cancer Nurs 36(1):52–59
Fenlon D, Addington-Hall J, O’Callaghan A, Clough J, Nicholls P, Simmonds P (2013) A survey of joint and muscle aches, pain, and stiffness comparing women with and without breast cancer. J Pain Symptom Manag 46(4):523–535
Partridge A, LaFountain A, Mayer E et al (2008) Adherence to initial adjuvant anastrazole therapy among women with early stage breast cancer. J Clin Oncol 26:556–562
Khan Q, Reddy P, Kimler B et al (2010) Effect of vitamin D supplementation on serum 25 hydroxy vitamin D levels, joint pains, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 119:111–118
Prieto-Alhambra D, Kassim Javiad M, Servitja S, Arden N, Martinez-Garcia M, Diez-Perez A, Albanell J, Tusquets I, Nogues X (2011) Vitamin D threshold to prevent aromotase inhibitor induced arthrlagia: a prospective study. Breast Cancer Res Treat 125:869–878
Shapiro A, Adlis S, Robien K, Kirstein M, Liang S, Richter S, Lerner RE (2016) Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). Breast Cancer Res Treat 155:501–512
Khan Q, Kimler B, Reddy P, Sharma P, Klemp J, Nydegger J, Yeh H, Fabian C (2017) Randomized trial of virtamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial. Breast Cancer Res Treat 166(2):491–500
Maksa L, Anderson J, Michaud K (2011) Measures of functional status and quality of life in rheumatoid arthritis: Health Assessment Questionnaire Disability Index (HAQ), Modified Health Assessment Questionnaire (MHAQ), Multidimensional Health Assessment Questionnaire (MDHAQ), Health Assessment. Arthritis Care Res 63(Suppl 11):S4–S13
Rastelli A, Taylor M, Gao F, Armamento-Villareal R, Jamalabadi-Majidi S, Napoli N, Ellis M (2011) Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat 129(1):107–116
van Groen M, ten Klooster P, Taal E et al (2010) Application of the health assessment questionnaire disability index to various rheumatic diseases. Qual Life Res 19(9):1255–1263
Bruce FJ (2003) The Stanford health assessment questionnaire: a review of its history, issues, progress, and documentation. J Rheumatol 30(1):167–178
Bruce B, Fries J (2003) The Stanford Health Assessment Questionnaire: dimensions and practical applications. Health Qual Life Outcomes 1(20):1–6
Khan Q, Reddy P, Kimler B, Sharma P, Baxa SE, O’Dea AP, Klemp JR, Fabian CJ (2010) Effect of vitamin D supplementation on serum 25 hydroxy vitamin D levels, joint pains, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 119:111–118
Niravath P, Chen B, Chapman J, Agarwal S, Welschhans R, Bongartz T, Kalari K, Shepherd L, Bartlett J, Pritchard K, Gelmon K, Ingle J (2018) Vitamin D levels, vitamin D receptor polymorphisms, and inflammatory cytokines in aromatase inhibitor-induced arthralgias: an analysis of CCTG MA.27. Clin Breast Cancer 18(1):78–87
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Dr. Nangia has had a consultant/advisory role with Puma, and she has received funding from Paxman Coolers. Dr. Ademuyiwa has had a consultant/advisory role with Immunomedics, AstraZeneca, Jounce, Eisai, and Best Doctors; she has received funding from Pfizer, Abbvie, Seattle Genetics, Immunomedics, and Polyphor. Dr. Ellis has had a consultant/advisory role with NanoString, Novartis, AstraZeneca, Pfizer, Abbvie, Sermonix, and Puma; he has stock ownership in Bioclassifier with Royalty income from Prosigna/NanoString. Dr. Osborne has had a consultant/advisory role with Puma, AstraZeneca, and Genentech; stock ownership in GENETEX; and funding from Puma. Dr. Rimawi has had a consultant/advisory role in MacroGenics, Daiichi, and Novartis; he has received funding from Novartis and Pfizer. Dr. Ma has had a consultant/advisory role with Pfizer, Novaris, and Lilly; she has received funding from Eisai, Puma, and Pfizer.
Ethical approval
All procedures and processes in this clinical trial comply with all regulatory laws in the United States, where the study was conducted. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Baylor College of Medicine Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Niravath, P., Hilsenbeck, S.G., Wang, T. et al. Randomized controlled trial of high-dose versus standard-dose vitamin D3 for prevention of aromatase inhibitor-induced arthralgia. Breast Cancer Res Treat 177, 427–435 (2019). https://doi.org/10.1007/s10549-019-05319-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-019-05319-4