Forteo for the Treatment of Unexplained Osteoporosis in Premenopausal Women

Idiopathic osteoporosis (IOP) is an uncommon disorder in which otherwise healthy young
individuals sustain one or more low-trauma fractures. In studies of IOP in men,
histomorphometric indices of bone formation are depressed, and affected men respond to
PTH(1-34) with robust increases in lumbar spine (LS) bone mineral density (BMD). This is the
beginning of the third year of an R01 (AR4989603) investigating the etiology and
pathogenesis, as well as the histomorphometric and bone microarchitectural features of IOP in
premenopausal women. There is evidence of markedly decreased bone formation and
microarchitectural deterioration with decreased mechanical competence/strength.

Teriparatide [PTH(1-34)] is an anabolic agent that stimulates bone formation and improves
bone microarchitecture. Based on findings, the investigators hypothesize that teriparatide
will significantly increase BMD and improve microarchitecture in premenopausal women with
IOP.

This is an open-label study of carefully characterized premenopausal women with IOP who are
participating in a NIH-funded study and who have fragility fractures or very low bone
density. Participants in the study will receive 18-24 months of teriparatide and the effects
on BMD and microstructure, bone mechanical competence, and bone turnover will be assessed. In
order to assess whether teriparatide stimulates bone formation to the same extent in women
with IOP as it does in normal women, the study will compare the short-term changes (2 and 4
weeks) in biochemical markers of bone formation in response to teriparatide between women
with IOP and normal women who are participating in another NIH-funded study as controls.

Inclusion Criteria:

- Premenopausal women of all races.

- Ages 20 to 48.

- Regular menses (at least 8 periods in the last 12 months).

- FSH < 20 mIU/ml during the early follicular phase, to exclude women in the
perimenopause.

- Fracture subjects: documented low trauma fracture(s) at age >= 18 (e.g., fracture
associated with a fall from a standing height or less).

- Low BMD subjects: DXA BMD T score less than or equal to 2.5 at the LS, total hip,
femoral neck or distal radius, who have not had a fracture.

- Control subjects: DXA BMD T score greater than or equal to 1.0 at the LS, total hip,
femoral neck and distal radius, who have not had a fracture.

- All subjects must use appropriate birth control methods to prevent pregnancy for the
duration of teriparatide treatment.

Exclusion Criteria:

- Secondary Causes of Osteoporosis.

- Disorders of mineral metabolism: primary or secondary hyperparathyroidism (serum
intact PTH > 65 pg/ml), vitamin D deficiency (serum 25OHD < 30 ng/ml), hypercalciuria
(>300 mg/g creatinine), Paget's disease, clinical osteomalacia, osteogenesis
imperfecta (OI).

- Recent pregnancy or lactation (within past year).

- Prolonged amenorrhea (> 6 months) during reproductive years (except during pregnancy
or lactation).

- History of anorexia nervosa.

- Malignancy, except cured basal or squamous cell skin carcinoma.

- Endocrinopathy: hyperthyroidism (elevated serum thyroxine and/or suppressed TSH),
untreated hypothyroidism, Cushing's syndrome, prolactin-secreting pituitary adenoma.

- Renal insufficiency (serum creatinine above upper limit of female normal range).

- Liver disease (AST, ALT, bilirubin, total alkaline phosphatase activity above upper
normal limit).

- Intestinal disorders (celiac disease, pancreatic insufficiency, inflammatory bowel
disease).

- History or current use of glucocorticoids, anticonvulsants, anticoagulants, diuretics,
methotrexate.

- Current use of depot preparations of progesterone or GnRH agonists.

- Current use of drug therapies for osteoporosis (estrogen preparations other than
contraceptives, raloxifene, bisphosphonates, calcitonin, PTH). Subjects who agree to
discontinue use of these medications will be eligible to participate 6 months after
discontinuing raloxifene or calcitonin, and 12 months after discontinuing
bisphosphonates. Total exposure to bisphosphonates must be < 1 year. Subjects who have
taken PTH at any time in the past will not be eligible.

- Additional contraindications to teriparatide use: Unexplained elevated total or bone
specific alkaline phosphatase or prior external beam or implant radiation therapy
involving the skeleton.