Zoledronic Acid in Aromatase Inhibitor Induced Musculoskeletal Symptoms

PRIMARY OBJECTIVES:

I. Percentage of women experiencing aromatase inhibitor associated musculoskeletal symptoms
(AIMSS) at 1, 3, 6, and 12 months after bisphosphonate therapy, as compared to historical
controls.

II. Change in Health Assessment Questionnaire Disability Index (HAQ-DI) score and 1, 3, 6 and
12 months, from baseline, among those receiving bisphosphonate, as compared to historical
controls.

SECONDARY OBJECTIVES:

I. Change in pain scores on visual analog scale (VAS) at 1, 3, 6 and 12 months, from
baseline, compared to historical controls.

II. Change in amount and/or frequency of oral analgesic use at 1, 3, 6 and 12 months from
baseline among those receiving bisphosphonate therapy, as compared to historical controls.

III. Number of patients who discontinue or change aromatase inhibitor (AI) therapy.

IV. Change in menopausal symptoms (NSABP-revised), hot flash frequency (HFRDIS),sleep quality
(PSQI), depression score (CESD) and overall quality of life (EuroQOL) in patients at 1, 3, 6
and 12 months from baseline, among those receiving bisphosphonate therapy, as compared to
historical controls.

V. Changes in plasma estrogen concentrations at 1, 3, 6 and 12 months from baseline, among
those receiving bisphosphonate therapy, as compared to historical controls.

VI. Change in bone mineral density (DEXA scan) at 12 months from baseline, among those
receiving bisphosphonate therapy, as compared to historical controls.

VII. Change in bone turn over markers (serum-C telopeptide, bone-specific alkaline
phosphatase, osteocalcin and urinary N-telopeptide) at 1, 3, 6 and 12 months from baseline,
among those receiving bisphosphonate therapy, as compared to historical controls.

VIII. Change in inflammatory markers (ESR, CRP, IL-1, IL-6, IL-8) at 1, 3, 6 and 12 months
from baseline, among those receiving bisphosphonate therapy, as compared to historical
controls.

OUTLINE: Patients receive zoledronic acid intravenously (IV) at months 1 and 6. Beginning 14
days after first zoledronic acid infusion, patients receive oral letrozole once daily for 12
months in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria

- Patients with histologically proven DCIS or stage I-III invasive carcinoma of the
breast that is estrogen and/or progesterone receptor positive by immunohistochemical
staining who are considering aromatase inhibitor therapy; women may receive the AI on
this study as initial adjuvant hormonal treatment or following tamoxifen; patients
must have completed any adjuvant chemotherapy; patients may have received preoperative
chemotherapy

- Postmenopausal status, defined as: >= 60 years of age; or < 60 years of age and
amenorrheic for >= 12 months prior to day 1 if intact uterus/ovaries; or < 60 years of
age, and the last menstrual period 6-12 months prior to day 1, if intact
uterus/ovaries and meets biochemical criteria for menopause (FSH and estradiol within
institutional standards for postmenopausal status); or < 60 years of age, without a
uterus, and meets biochemical criteria for menopause (FSH and estradiol within
institutional standards for postmenopausal status); or < 60 years of age and history
of bilateral oophorectomy; or prior radiation castration with amenorrhea for at least
6 months; < 60 years of age and taking medication designed to suppress ovarian
function and meets biochemical criteria for menopause (estradiol levels within
institutional standards for postmenopausal status; women would have had to be taking
the drug for at least 30 days prior to day 1)

- ECOG performance status 0-2

- Patient is aware of the nature of her diagnosis, understands the study regimen, its
requirements, risks, and discomforts, and is able and willing to sign an informed
consent form

Exclusion Criteria

- Concurrent use of hormone replacement therapy

- Concurrent use of tamoxifen; patients taking tamoxifen must discontinue the drug prior
to first dose of zoledronic acid

- Concurrent use of other selective estrogen receptor modulator (SERM) such as
raloxifene

- Concurrent consumption of soy supplements; routine dietary consumption of soy
containing foods will be permitted

- Prior use of an aromatase inhibitor in any setting

- Current bisphosphonate use (oral or intravenous); prior bisphosphonate users would be
eligible as long as the use was > 1 month ago for oral bisphosphonates and/or > 12
months ago for intravenous bisphosphonates, prior to starting study treatment

- Moderate to severe renal impairment (serum creatinine greater than 2 mg/dL or
creatinine clearance less than 50 mL/min)

- Hypersensitivity to letrozole or zoledronic acid or any of its excipients

- Concomitant treatment with oral or intravenous corticosteroids

- Current active dental problems including infection or the teeth or jawbone (maxilla or
mandibular); dental or fixture trauma, or a current or prior diagnosis of
osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after
dental procedures

- Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants)