Forteo Trial on Idiopathic Osteoporosis in Premenopausal Women

Condition(s) targeted: Adult Idiopathic Generalized Osteoporosis

Intervention: Teriparatide (Drug); Saline Placebo (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Elizabeth Shane

Official(s) and/or principal investigator(s):
Elizabeth Shane, MD, Principal Investigator, Affiliation: Columbia University
Adi Cohen, MD, Study Director, Affiliation: Columbia University
Emily M Stein, MD, Study Director, Affiliation: Columbia University

Overall contact:
Mariana Bucovsky, BA, Phone: 212-305-7225, Email: mb3523@columbia.edu

Idiopathic osteoporosis (IOP) is defined as osteoporosis that affects young, otherwise completely healthy individuals with no secondary cause of bone loss. In the course of our prior research with premenopausal women with IOP, the investigators have shown 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 features of bone quality in premenopausal women with IOP. There is currently no FDAapproved therapy for IOP in premenopausal women. However, teriparatide (Forteo) 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. Because IOP in premenopausal women is an orphan disease, with an estimated prevalence of about 113,000 in the United States, pharmaceutical companies are unlikely to support development of therapies for this indication. Therefore the major objective of this protocol is to establish the safety and efficacy of teriparatide in premenopausal women with IOP in a phase 2 clinical trial. All subjects will receive teriparatide as part of the study, but a randomly selected group of patients (10) will receive one year of placebo injections first before starting their two years of treatment. The remainder of subjects (30) will receive active drug only for two years.

Official title: Randomized Controlled Trial of Teriparatide for the Treatment of Idiopathic Osteoporosis in Premenopausal Women

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Change in lumbar spine bone mineral density (LS-BMD)

Detailed description: Funding Source: FDA-OOPD 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 an NIH-funded study of premenopausal women with IOP (R01 AR49896, IRB AAAA9245), the investigators have shown 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 1-34, hPTH(1-34) or teriparatide (TPTD), terms which will be used interchangeably in this proposal, 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. Our 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. This study is exploratory and will not support any new labeling claims for Forteo in the premenopausal patient population.

Minimum age: 20 Years. Maximum age: 45 Years. Gender(s): Female.

Criteria:

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 GCs, anticonvulsants, anticoagulants, methotrexate, depot

progesterone, 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.

Mariana Bucovsky, BA, Phone: 212-305-7225, Email: mb3523@columbia.edu

Creighton University, Omaha, Nebraska 68131, United States; Recruiting
Phone: 402-280-4470
Robert Recker, MD, Principal Investigator
Joan Lappe, MD, Sub-Investigator

Columbia University Medical Center, New York, New York 10032, United States; Recruiting
Phone: 212-305-7225
Elizabeth Shane, MD, Principal Investigator
Adi Cohen, MD, Sub-Investigator
Emily M Stein, MD, Sub-Investigator

Columbia University, Dept of Medicine, Division of Endocrinology website

Starting date: January 2012
Last updated: April 6, 2015