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A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial

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Abstract

Purpose

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS.

Methods

In the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively.

Results

From 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density.

Conclusions

Compared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.

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Acknowledgements

Zoledronic acid and letrozole were provided by Novartis.

Funding

Breast Cancer Research Foundation, National Institutes of Health [P30 CA06973].

Author information

Author notes

  1. Aditya Bardia

    Present address: Massachusetts General Hospital Cancer Center, Boston, USA

  2. Robert S. Miller

    Present address: American Society of Clinical Oncology, Alexandria, USA

  3. Nora Lynn Henry

    Present address: University of Utah, Salt Lake City, USA

Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Cesar A. Santa-Maria, Aditya Bardia, Amanda L. Blackford, Claire Snyder, Roisin M. Connolly, John H. Fetting, Stacie C. Jeter, Katie Quinlan, Gary L. Rosner, Shannon Slater, Antonio C. Wolff, Jane Zorzi & Vered Stearns

  2. University of Michigan Comprehensive Cancer Center, Ann Arbor, USA

    Daniel F. Hayes & Nora Lynn Henry

  3. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, USA

    Anne Nguyen & Anna Maria Storniolo

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  1. Cesar A. Santa-Maria
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Corresponding author

Correspondence to Vered Stearns.

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Conflict of interest

CAS has received research funding from Medimmune and Pfizer. VS received research funding from Abbvie, Medimmune, Novartis, Pfizer, and PUMA. CS received research funding from Genentech (to the institution); speaking honorarium from CaretMD and Tower Health System; royalties from UptoDate; and travel support from Optum. RC received research funding from Merck, Novartis, Merrimack, Clovis, Genentech, and PUMA. AW has received research funding from Pfizer. NLH received research funding from AstraZeneca. All remaining authors have declared no conflict of interest.

Electronic supplementary material

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10549_2018_4811_MOESM1_ESM.jpg

Subgroup analysis assessing AIMSS at any time point according to age, prior taxanes, prior tamoxifen, BMI, and baseline VAS scores. Supplementary material 1 (JPG 430 KB)

Supplementary material 2 (DOCX 12 KB)

Supplementary material 2 (DOCX 12 KB)

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Santa-Maria, C.A., Bardia, A., Blackford, A.L. et al. A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial. Breast Cancer Res Treat 171, 121–129 (2018). https://doi.org/10.1007/s10549-018-4811-1

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