Zoledronic Acid for Osteoporosis in the Elderly

This is a 2-year, randomized, double-blind, calcium/vitamin D-controlled clinical trial of a
single dose of therapy with at least 12 months follow-up. All participants will receive
calcium and vitamin D throughout the trial. At baseline, 190 women will be randomized in a
1:1 allocation to zoledronic acid (group 1) or zoledronic acid placebo (group 2). At the end
of 24 months, women will be followed to gather data on longer term fragility fracture rates
and survival until all participants have completed 24 months of follow-up.

Inclusion Criteria:

- We will include elderly women 65 years and older if they reside in a nursing home or
an assisted living facility and have a known history of osteoporosis, as determined
by history of an adult fragility fracture or bone mineral density criteria for
osteoporosis (T-score -2.5 at the total hip, femoral neck or spine) or low bone mass
(T-score < -2.0 at the total hip, femoral neck or spine, consistent with the National
Osteoporosis Foundation Treatment guidelines). If a participant's spine and or hip
are not evaluable (due to surgery, calcifications, artifact in the scan area,
scoliosis, etc.), they may be included in the study with a T-score of ≤ -2.0 at the
forearm.

- Elders will be chosen without consideration of ethnic or racial background. We chose
frail, institutionalized women because 70-85% of them have osteoporosis and this age
group is substantially under-treated.

- We will include all who qualify, if they are able to weight bear or assist with
transfer to chair, to endure that the results have maximum generalizability to the
nursing home population as a whole.

Exclusion Criteria:

- Children will be excluded because they are not frail, institutionalized elders.

- Men will be excluded because they do not become postmenopausal and are less likely to
become osteoporotic.

- We will exclude institutionalized women with subacute illnesses who are not expected
to survive or who will be discharged in less than 2 years.

- We will also exclude patient with a contraindication to bisphosphonate, such as
hypocalcemia, allergy, pervious adverse event (excluding gastrointestinal disorders),
or currently on an oral bisphosphonate.

- We will exclude patients with a calculated creatinine clearance of < 30 ml/mm.

- We will exclude women scheduled for or in need of a tooth extraction as this
procedure has been associated with osteonecrosis of the jaw in patients with cancer
given multiple coursed of high dose intravenous bisphosphonates.

- We will screen for these conditions by detailed history, physical exam (including
dental exam), chart review, and baseline laboratory analyses, including
BUN/creatinine, liver function tests, TSH, calcium, PTH, 25-hydroxyvitamin D,
alkaline phosphatase and baseline calculated creatinine clearance. Participants with
vitamin D levels < 20 ng/ml will be treated with vitamin D 50,000 IU/wk for 8 weeks
in addition to calcium. Vitamin D will be rechecked and the patient will be enrolled
if the vitamin D level is > 20 ng/ml.

- Patients will be allowed to continue on certain medications known to affect bone and
mineral metabolism (e.g. glucocorticoids, anticonvulsants) because their use is
common in this population. (In our facilities, 2.9% of patients use glucocorticoids
and 7.2% use anti-epileptic drugs.) In addition, women who have been treated in the
past or present with osteoporosis agents, such as estrogen/progesterone, raloxifene,
and calcitonin, will be allowed to participate and continue on these therapies if
prescribed by their physician. However, if patients are currently on or have been on
bisphosphonates for greater than 1 year in the previous 2 years prior to enrollment,
they will be excluded as some bisphosphonates are long acting.

- Patients will be allowed to wear hip pads if prescribed by their physician. If they
are on parathyroid hormone, they may participate, but will be told that monotherapy
with parathyroid hormone is more beneficial than combination therapy with parathyroid
hormone and alendronate, as we have previously demonstrated.