Zoledronic Acid for Osteoporotic Fracture Prevention (ZEST II)

Although close to 85% of frail women in long-term care (LTC) facilities have osteoporosis and
the risk of osteoporotic fractures is nearly 10 times that of community dwelling elderly, few
are treated and studies are scarce. It is postulated that in frail, LTC women an annual
infusion of zoledronic acid, an antiresorptive therapy for osteoporosis, will:

1. be effective demonstrated by fracture reduction;

2. be safe.

To address these hypotheses, up to 1000 female LTC residents age 65 and older will be
screened in order to enroll 514 eligible for randomization in a 3 year, randomized,
double-blind, calcium and vitamin D controlled trial with the antiresorptive agent zoledronic
acid. Use of an intravenous, once yearly agent avoids concerns of oral bisphosphonate side
effects, poor absorption and burden on staff. Participants will reside in the long-term care
settings associated with the Division of Geriatric Medicine, University of Pittsburgh and
will include women with multiple comorbid conditions, functional and cognitive impairment,
and limited mobility.

Inclusion Criteria:

- women age ≥65 years including those using assistive devices to maximize
generalizability if they:

1. Reside in long-term care (LTC);

2. Have:

- osteoporosis by axial bone density (spine, hip or forearm bone mineral
density (BMD) T-score ≤ -2.5 SD); or

- a previous adult fragility fracture of the spine or hip; or,

- would be treated based on FRAX National Osteoporosis Foundation (NOF)
treatment thresholds of a 10 year risk of ≥ 20% for a major osteoporotic
fracture or ≥ 3% for hip fracture using femoral neck BMD.

Exclusion Criteria:

- Men because osteoporosis is less common in men and our initial ZEST 1 study only
included women.

- Institutionalized women with subacute illnesses surviving or discharged in < 3 years.

- Women currently on bisphosphonate, denosumab, or teriparatide therapy or who have been
on a bisphosphonate for greater than 1 year during the previous 2 years because
bisphosphonates are long acting.

- Patients with a calculated creatinine clearance < 35 ml/min or who have a
contraindication for bisphosphonates (allergy, hypocalcemia).