Zoledronic Acid for Osteoporotic Fracture Prevention (ZEST II)

Study Overview
=================
Brief Summary
-----------------
The goal of this study is to perform the first fracture reduction clinical trial with a potent antiresorptive agent (intravenous zoledronic acid) in the most vulnerable long-term care population.

Detailed Description
-----------------
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: be effective demonstrated by fracture reduction; be safe. To address these hypotheses, up to 1000 female LTC residents age 65 and older will be screened in order to enroll 310 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.

Official Title
-----------------
ZEST II for Osteoporotic Fracture Prevention

Conditions
-----------------
Osteoporotic Fractures, Osteoporosis, Postmenopausal

Intervention / Treatment
-----------------
* Drug: Zoledronic acid
* Dietary Supplement: vitamin D
* Dietary Supplement: calcium
* Other: Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: women age ≥65 years including those using assistive devices to maximize generalizability if they: Reside in long-term care (LTC); 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).

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Medication Group<br>Annual dose: intravenous zoledronic acid (Reclast) 5.0 mg; vitamin D (800 IU/daily) and calcium (approximately 1200 mg/daily, dietary + supplements) | Drug: Zoledronic acid<br>* Annual intravenous 5.0 mg<br>* Other names: Reclast;Dietary Supplement: vitamin D<br>* 800 IU daily<br>Dietary Supplement: calcium<br>* approximately 1200 mg (dietary and supplement)<br>|
| Placebo Comparator: Placebo Group<br>Annual dose: intravenous saline; vitamin D (800 IU/daily and calcium (approximately 1200 mg/daily, dietary + supplements) | Dietary Supplement: vitamin D<br>* 800 IU daily<br>Dietary Supplement: calcium<br>* approximately 1200 mg (dietary and supplement)<br>Other: Saline<br>* Annual intravenous saline placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-traumatic Incidental Fractures (Vertebral and Nonvertebral [Identified by X-ray, CT, MRI, VFA Imaging] Per Person-year) | Number of fractures divided by number of person-years. Effectiveness of fracture reduction will be demonstrated by total non-traumatic incidental fractures (vertebral and nonvertebral [identified by x-ray, CT, MRI, VFA imaging) except those viewed as severe trauma (fall from a height higher than a stool or chair or severe trauma other than a fall), cancer-related or fractures of the toes, finger or facial bones. | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bone loss, Frail Geriatric Women, Nursing Home Patients, Long-term Care Patients, Osteoporosis, Osteoporotic Fractures