Breast Cancer Research and Treatment

, Volume 171, Issue 1, pp 121–129 | Cite as

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

  • Cesar A. Santa-Maria
  • Aditya Bardia
  • Amanda L. Blackford
  • Claire Snyder
  • Roisin M. Connolly
  • John H. Fetting
  • Daniel F. Hayes
  • Stacie C. Jeter
  • Robert S. Miller
  • Anne Nguyen
  • Katie Quinlan
  • Gary L. Rosner
  • Shannon Slater
  • Anna Maria Storniolo
  • Antonio C. Wolff
  • Jane Zorzi
  • Nora Lynn Henry
  • Vered StearnsEmail author
Clinical trial



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.


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.


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.


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.


Aromatase inhibitors Arthralgias Bisphosphonates Survivorship care Quality of life 



Zoledronic acid and letrozole were provided by Novartis.


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

Compliance with ethical standards

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.

Supplementary material

10549_2018_4811_MOESM1_ESM.jpg (431 kb)
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)
10549_2018_4811_MOESM2_ESM.docx (13 kb)
Supplementary material 2 (DOCX 12 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Cesar A. Santa-Maria
    • 1
  • Aditya Bardia
    • 1
    • 4
  • Amanda L. Blackford
    • 1
  • Claire Snyder
    • 1
  • Roisin M. Connolly
    • 1
  • John H. Fetting
    • 1
  • Daniel F. Hayes
    • 2
  • Stacie C. Jeter
    • 1
  • Robert S. Miller
    • 5
  • Anne Nguyen
    • 3
  • Katie Quinlan
    • 1
  • Gary L. Rosner
    • 1
  • Shannon Slater
    • 1
  • Anna Maria Storniolo
    • 3
  • Antonio C. Wolff
    • 1
  • Jane Zorzi
    • 1
  • Nora Lynn Henry
    • 2
    • 6
  • Vered Stearns
    • 1
    Email author
  1. 1.Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins School of MedicineBaltimoreUSA
  2. 2.University of Michigan Comprehensive Cancer CenterAnn ArborUSA
  3. 3.Indiana University Melvin and Bren Simon Cancer CenterIndianapolisUSA
  4. 4.Massachusetts General Hospital Cancer CenterBostonUSA
  5. 5.American Society of Clinical OncologyAlexandriaUSA
  6. 6.University of UtahSalt Lake CityUSA

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