Forteo Trial on Idiopathic Osteoporosis in Premenopausal Women

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.

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 12 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.

• Drug: Teriparatide
  Daily injection of 20 mcg teriparatide for the treatment of idiopathic osteoporosis for 24 months.
  Other Name: Forteo
• Drug: Saline Placebo
  Daily injection of saline placebo for 12 months, followed by teriparatide treatment for 24 months.

• Active Comparator: Teriparatide (Forteo)
  Daily injection of Teriparatide for treatment of idiopathic osteoporosis
  Intervention: Drug: Teriparatide
• Placebo Comparator: Placebo saline injection
  Daily injection of saline placebo for 12 months, followed by 24 months of teriparatide treatment for idiopathic osteoporosis.
  Intervention: Drug: Saline Placebo

Inclusion Criteria:

• Premenopausal women, aged 20-45, with regular menses and no historical or biochemical secondary cause of osteoporosis; the lower age limit is to ensure epiphyses are fused, the upper to make it less likely that women will enter menopause during the study. All subjects under age 25 will be screened prior to drug administration to rule out open epiphyseal plates.
• Documented adult fractures judged to be low-trauma (trauma equivalent to a fall from a standing height or less) and/or T < -2.5 or Z score <-2.0 at the LS, FN or TH. 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 BMD defined as a T-score or Z-score greater than or equal to -1.5.
• Premenopausal women above the age of 35 years should have a history of fracture AND/OR low BMD defined as Z-score < -2.0. Women above age 35 may also be enrolled on the basis on low BMD alone, without presence of prior low trauma fracture.
• Must be willing to use effective contraception throughout the period of study drug administration

Exclusion Criteria:

• History of any condition that increases the risk of osteosarcoma (Paget's disease, skeletal irradiation)
• Early follicular phase serum FSH>20 mIU/ml (to exclude perimenopausal women)
• Disorders of mineral metabolism: 1o/2 o hyperparathyroidism, osteomalacia, osteogenesis imperfecta (OI) or Ehlers Danlos (ED). Subjects will not routinely undergo genetic testing for OI or ED as part of their screening evaluation. However, each subject will have a detailed medical and family history and a complete physical examination by one of the physician investigators. Women with historical features or physical examination findings suggestive of OI or ED will be referred for genetic evaluation. If the genetic evaluation is positive for OI or ED, the subject will be excluded from participation.
• Vitamin D deficiency (serum 25-OHD<20 ng/ml). Women with levels of 20-30 ng/ml will be eligible after treatment with vitamin D has resulted in levels >30 ng/ml.
• Pregnancy or lactation within past 12 months
• Prolonged amenorrhea (> 6 months) during reproductive years (except pregnancy or lactation)
• History of an eating disorder (anorexia nervosa, bulimia)
• Malignancy, except cured basal or squamous cell skin carcinoma
• Endocrinopathy: new onset untreated hyperthyroidism, hypothyroidism, Cushing's syndrome, prolactinoma
• 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/current GCs, anticonvulsants, anticoagulants, methotrexate, depot progesterone, GnRH agonists
• 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 or zoledronate. Total bisphosphonate exposure must be < 1 year. Subjects who have taken TPTD or zoledronate in the past will not be eligible.