Cyclic Versus Daily Teriparatide on Bone Mass

Osteoporosis is a serious bone disease that has become an important public health problem. It
causes significant loss of bone mass and increases the risk of both fracture and
architectural problems with the skeleton. Until recently, the treatments available for
osteoporosis primarily prevented further deterioration of bone by reducing the rate of
remodeling within the skeleton. This can reduce the risk of fracture by approximately 50%.
Teriparatide is a new type of drug for people with osteoporosis who are at high risk of
fracture. Teriparatide stimulates bone remodeling and can correct the underlying
architectural and bone mass abnormalities that are characteristic of osteoporosis. This study
will compare continuous versus cyclic treatment with teriparatide combined with alendronate,
another drug for osteoporosis, or teriparatide alone in women with osteoporosis.

All participants have completed a parent study of two years that included a screening visit
with a physical exam, blood draw, x-rays, EKG, and distribution of calcium and vitamin D
supplements. Participants will be separated into two groups according to the treatment they
have undergone over the year prior to study entry. Participants who have taken alendronate
for at least 1 year prior to study entry will be assigned to Protocol 1. Participants who
have not previously taken alendronate will be assigned to Protocol 2. Participants in both
protocols will be randomly assigned to one of the following three biopsy groups:
pre-treatment; early; or late. Participants in the pre-treatment biopsy group will have a
bone biopsy before treatment begins. Those participants in the early biopsy group will have a
biopsy at Week 7 of treatment, and those in the late group will have a biopsy at Month 7.5 of
treatment.

Participants will also be randomly assigned to one of three treatment schedules. Participants
in Protocol 1 may be assigned to receive alendronate alone for 24 months; teriparatide daily
plus alendronate for 24 months; or teriparatide daily on and off for 3 months at a time plus
alendronate for 24 months. Participants in Protocol 2 may be assigned to receive only the
supplements they were given during the screening visit; teriparatide daily plus alendronate
for 24 months; or teriparatide daily on and off for 3 months at a time for 24 months.
Participants will attend assessment visits at Weeks 4 and 7 and Months 3, 5, 6, 7.5, 9, 12,
15, 18, 21, and 24. Visits may include bone turnover measurements, bone mass scans, walking
tests, questionnaires, CT scans, and blood draws.

A recently funded extension study will extend the treatment period from 24 to 48 months for
all consenting. If the individual was assigned to teriparatide daily (with or without
alendronate), they will be given alendronate for the 24 to 48 month time period. If the
individual was assigned to cyclic teriparatide, they will continue cyclic therapy foro the
24-48 month period (with or without alendronate).

Inclusion Criteria:

- Diagnosis of osteoporosis or T score below -2 plus one or more osteoporosis related
fractures

- Two measurable vertebrae between L1 and L4

- Willing to undergo a single iliac crest biopsy after administration of 4 tetracycline
labels

Exclusion Criteria:

- Secondary causes of osteoporosis or presence of a skeletal disorder other than
osteoporosis

- Uses drugs likely to affect skeletal or calcium homeostasis

- Multiple vertebral fractures or severe degenerative changes with fewer than two
evaluable vertebrae

- Unwilling to undergo a single iliac crest biopsy

- History of allergy to tetracyclines, exposure to tetracyclines within the last year,
or any remote long term use of tetracyclines

- Current use of anti-resorptive medicines (other than alendronate for half the female
participants)

- Use of hormone therapy, estrogen therapy, raloxifene, or calcitonin within 6 months
before study entry

- Use of any bisphosphonate for more than 3 months within 2 years before study entry
(only applies to participants in Groups 4, 5, and 6)

- History of a kidney stone within 5 years before study entry or any history of multiple
kidney stones

- Hypercalcemia, hypercalciuria, or elevated parathyroid hormone (reduced
25-hydroxyvitamin D will be corrected prior to admission)

- Esophageal ulceration or stricture or known hypersensitivity to bisphosphonates

- History of external radiation therapy

- Unlikely or unable to complete the study, as determined by the investigators

- Illicit drug use or excessive alcohol consumption