Forteo Trial on Idiopathic Osteoporosis in Premenopausal Women

Osteoporosis is a skeletal disorder characterized by reduced bone strength that predisposes
to an increased risk of fracture. Osteoporosis affects postmenopausal women and elderly men
and is very unusual in healthy individuals under age 50. Moreover, more than 90% of young men
and premenopausal women with osteoporosis have a secondary cause of bone lose, such as an
underlying disorder (e.g., hypogonadism) or a medication exposure (e.g., glucocorticoids,
antiepileptic drugs), that either interfered with acquisition of peak bone mass or caused
excessive bone loss thereafter. Idiopathic osteoporosis (IOP) is defined as osteoporosis that
affects young, otherwise completely healthy individuals with intact gonadal function and no
secondary cause of bone loss. First described by Fuller Albright in 1944, IOP is an uncommon
condition with an estimated annual incidence of 0.4 cases per 100,0003. IOP predominantly
affects Caucasians, who generally present in their mid-30s with one more low trauma
fractures.

In the course of a previously conducted NIH-funded study of premenopausal women, the
investigators demonstrated that women with IOP have low areal bone mineral density (aBMD) at
the spine, hip and forearm compared to normal women. Additionally, using noninvasive high
resolution imaging of the central and peripheral skeleton and detailed analyses of transiliac
crest bone biopsies, the investigators identified several distinctive and consistent features
of bone quality in premenopausal women with IOP: thin cortices, lower trabecular volumetric
bone mineral density (vBMD), fewer trabecular plates, fewer and longer trabecular rods,
decreased connectivity between rods and plates, lower mineralization density and lower
estimated stiffness of cancellous bone. Bone remodeling and biochemical indices of mineral
metabolism did not differ between IOP subjects and controls.

Although not every woman with IOP requires pharmacologic intervention, many have sustained
multiple low-trauma fractures or have extremely low bone mineral density (BMD). There is
currently no FDA-approved therapy for IOP in premenopausal women, therefore a safe and
effective therapy is urgently needed. Bisphosphonates are one therapeutic option but the
associated gains in BMD are primarily due to reduction in the remodeling space and increased
mineralization of bone rather than improvements in microarchitecture, an important
consideration as microarchitectural deficits are a consistent feature of IOP in premenopausal
women, while remodeling activity is most commonly normal or low. Furthermore, potential
teratogenic effects limit the safety of bisphosphonates in premenopausal women.

However, anabolic therapy with human recombinant parathyroid hormone (hPTH) 1-34 (or
teriparatide (TPTD)), has been shown to improve bone mass and microarchitecture in
postmenopausal women and is approved for men with primary or idiopathic osteoporosis, as well
as men, premenopausal and postmenopausal women with glucocorticoid-induced osteoporosis.
TPTD, on the other hand, increases bone formation and BMD, while improving microarchitecture
and strength. Moreover, TPTD has been shown to increase BMD in men with IOP, in premenopausal
women with glucocorticoid-induced osteoporosis (GIOP) and to prevent bone loss in
premenopausal women with nafarelin-induced acute estrogen deficiency. Although there have
been no studies evaluating TPTD in estrogen-replete premenopausal women with IOP, data from
studies of hPTH(1-34) in postmenopausal women on estrogen are relevant to this proposal.
These studies found increased aBMD at the LS and of lesser magnitude at the hip, as well as
major reductions in vertebral fracture. Also important, BMD remained stable in postmenopausal
women on estrogen followed for two years after TPTD discontinuation. Lane et al. reported
similar results in postmenopausal women with GIOP on estrogen. These two studies suggest that
in estrogen-replete premenopausal women with IOP, increases in bone mass resulting from TPTD
will be sustained after the course of therapy is completed.

The major objective of this protocol is a therapeutic one, namely to establish the safety and
efficacy of TPTD in premenopausal women with IOP in a phase 2 clinical trial. The
investigators hypothesize that anabolic therapy with teriparatide will improve areal and vBMD
in premenopausal women with IOP. The investigators also hypothesize that teriparatide will
restore abnormal microarchitecture toward normal and improve other aspects of bone quality in
premenopausal women with IOP. The primary aim of this research study will be to establish the
efficacy and safety of 6 months of teriparatide versus placebo in premenopausal women with
IOP. The secondary aim is to determine the extent to which 12 and 24 months of teriparatide
improves areal and volumetric BMD, bone microarchitecture and stiffness compared to baseline
measures in premenopausal women with IOP. This study will have high impact on clinical
practice as it pertains to the management of premenopausal women with IOP.

Inclusion Criteria:

- Premenopausal women, aged 20-45, with regular menses and no historical or biochemical
secondary cause of osteoporosis.

- Documented adult fractures judged to be low-trauma.

- Must be willing to use effective contraception throughout the period of study drug
administration.

Inclusion Criteria - vary slightly based on age category:

- Premenopausal women ages 20-35 years must have at least one major osteoporotic
fracture (excluding fractures of fingers, toes and face) and low Bone Mineral Density
(BMD).

- Premenopausal women above the age of 35 years should have a history of fracture and/or
low BMD.

Exclusion Criteria:

- History of any condition that increases the risk of osteosarcoma

- Early follicular phase serum

- Disorders of mineral metabolism

- Suspicion of osteomalacia

- Vitamin D deficiency

- Pregnancy or lactation within past 12 months

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

- Prior eating disorder

- Malignancy, except cured basal or squamous cell skin carcinoma

- Endocrinopathy: new onset untreated hyperthyroidism, hypothyroidism, Cushing's
syndrome, prolactinoma

- Renal insufficiency

- Liver disease

- Intestinal disorders

- History/current glucocorticoids (GCs), anticonvulsants, anticoagulants, methotrexate,
depot progesterone, Gonadotrophin-releasing hormone (GnRH) agonists

- Oral glucocorticoid use (subject will not be excluded if used dose equivalent to less
than prednisone 5 mg for <3 months).

- Current anticoagulant use or low molecular weight

- Depo Provera use (subjects will not be excluded if used at age>20, >5 years ago)

- Drugs for osteoporosis (raloxifene, bisphosphonates, denosumab, calcitonin, TPTD).
Subjects who discontinue these medications will be eligible 3 months after stopping
raloxifene or calcitonin, 12 months after stopping alendronate, risedronate,
ibandronate, or pamidronate and 18 months after stopping denosumab. Subjects with
prior use of zoledronate may be eligible if received only one dose >4 years ago. Total
bisphosphonate exposure must be < 1 year. Subjects who have taken TPTD in the past
will not be eligible unless used for <3 months, > 2 years ago.