Forteo Trial on Idiopathic Osteoporosis in Premenopausal Women
Condition: Adult Idiopathic Generalized Osteoporosis
MeSH terms: Osteoporosis
Study type: Interventional
Phase: Phase 2

Summary: 
      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 FDA-approved 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.

      Funding Source - FDA OOPD
    

Detailed description: 
      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.
    

Intervention name(s): Teriparatide; Saline Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Daily injection of 20 mcg teriparatide for the treatment of idiopathic osteoporosis for 24 months.; Daily injection of saline placebo for 6 months, followed by teriparatide treatment for 24 months.
Other intervention name(s): Forteo; TPTD; Placebo
Intervention MeSH terms: Teriparatide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: osteoporosis; premenopausal; forteo; idiopathic; Idiopathic Osteoporosis in Premenopausal Women