Comparison Study of PTHrP and PTH to Treat Osteoporosis
Condition: Osteoporosis
MeSH terms: Osteoporosis
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a three month comparison trial of standard dose parathyroid hormone (PTH) (1-34) and
      two different doses of Parathyroid Hormone-related Protein (PTHrP) (1-36). The investigators
      want to to demonstrate that daily subcutaneous injection of PTHrP (1-36) in postmenopausal
      women with osteoporosis stimulates bone formation to the same or greater degree than PTH
      (1-34) but with less bone resorption.
    

Detailed description: 
      Osteoporosis is a metabolic bone disease characterized by low bone mass and structural
      deterioration of bone tissue. It results from failure of osteoblasts to form sufficient new
      bone, from an excessive rate of osteoclastic bone resorption, or from the combination of both
      processes. The resultant bone fragility leads to an increased susceptibility to fractures,
      especially of the hip, spine and wrist. There is an increased mortality rate following both
      hip and vertebral fractures, and the presence of one fracture is a potent risk factor for
      future fractures. This leads to a decline in the quality of life and an associated loss of
      independence among the millions of individuals in the United States and worldwide afflicted
      with the disease. There is an additional population at an increased risk for fractures due to
      a less severe loss of bone mass, known as osteopenia (1). Already ten million individuals in
      the United States are estimated to have the disease and thirty four million more are at
      increased risk due to low bone mass (1).

      Approved pharmacological treatments for postmenopausal osteoporosis include two classes of
      drugs: the antiresorptive and the anabolics (2). The antiresorptive include estrogen,
      calcitonin, selective estrogen receptor modulators, and bisphosphonates. The antiresorptive
      medications prevent bone loss by inhibiting both osteoclastic bone resorption and formation,
      by slowing bone turnover, and by allowing for increased mineralization of osteoid (2). The
      increase in bone mineral density from the antiresorptive agents is generally reported to be
      in the range of 2-8% over 1-7 years (3-7).

      There is only one anabolic agent that is presently approved by the FDA for treatment for
      osteoporosis: parathyroid hormone, PTH (1-34), or teriparatide. PTH(1-34) was approved by the
      FDA in 2002 and it acts by increasing bone density by stimulating the PTH-1 receptor. This
      induces an increase in osteoblast mediated bone formation and osteoclast mediated bone
      resorption. Daily subcutaneous PTH is anabolic as there is stimulation of bone formation to a
      greater extent than bone resorption. The overall net result of biosynthetic PTH (1-34) is an
      increase in bone mineral density and a decrease in fractures (8). Daily PTH(1-34) treatment
      has been shown to effectively reduce the risk of both vertebral and nonvertebral fractures.
      Measurements of bone mineral density (BMD) of the lumbar spine (LS) resulted in an increase
      in bone density of 9 percent when compared to placebo (9). A daily 20 microgram dose of
      subcutaneous PTH(1-34) reduced the risk of getting two or more vertebral fractures by 77%,
      and the risk of at least one moderate or severe fracture was reduced by 90 and 78%
      respectively (9). Additionally, one vertebral fracture was prevented for every 12 patient
      years of treatment, and women were 35% less likely to have one or more new nonvertebral
      fragility fractures (9).

      Parathyroid hormone-related protein or PTHrP is a protein peptide that was first isolated in
      1987 as the factor responsible for the syndrome of humoral hypercalcemia of malignancy (HHM)
      (10-14). PTHrP is found in almost every tissue and cell type in the body, and appears to
      regulate cellular proliferation, survival, and differentiation in normal tissue as well as in
      malignancies (15-16). As the name implies, PTHrP is similar to PTH. Both peptides bind to the
      same receptor, PTH-1 R, and activate downstream signaling pathways causing similar post
      receptor effects (17).

      Since PTH is a potent anabolic agent, we hypothesize that PTHrP may act in an anabolic
      fashion as well. We are seeking to demonstrate in this study that PTHrP acts as an anabolic
      agent in the treatment of osteoporosis with similar or better efficacy than PTH in respect to
      bone formation but with less bone resorption and fewer side effects, such as hypercalcemia.

      The current studies are a sequel to initial phase 1 trials assessing the efficacy and safety
      of daily subcutaneous injection of PTHrP on the human skeleton. Previous studies have
      demonstrated that a single daily injection of ~ 400 mcg/day of PTHrP (1-36) in postmenopausal
      women on estrogen with osteoporosis led to a 4.7% increase in lumbar spine bone mineral
      density (BMD) after three months and all subjects were free of hypercalcemia or other adverse
      effects (18). In contrast with PTH, the doses of PTHrP are much larger, yet well-tolerated,
      and the increments in spine BMD are large and rapid with some subjects showing increases in
      spine BMD of 6-8% in as soon as three months in studies done thus far (18). PTHrP appears to
      selectively stimulate bone formation without stimulating bone resorption (18). This exciting
      observation may point towards PTHrP being a pure skeletal anabolic agent (21). Preliminary
      data analysis from a more recent three week dose escalation trial indicates demonstrates that
      the dose of 500 mcg/day of PTHrP causes 38% increase in P1NP and a 20% decrease in CTX
      indicating far greater bone formation than bone resorption with no hypercalcemia. At 625
      mcg/day there were similar increases in P1NP with hypercalcemia in only 10% of subjects and
      hypercalcuria in 20%. In contrast in subjects receiving 750 mcg/day 50% developed
      hypercalcemia requiring early termination. The P1NP and CTX data from the three week dose
      escalation trial was used for both determining dose and sample size calculations for this
      study.
    

Intervention name(s): Parathyroid hormone related protein (1-36); Parathyroid hormone related protein(1-36); Parathyroid hormone (1-34)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): PTHrP (1-36) 400 micrograms / day administered subcutaneously for 3 months; PTHrP(1-36)600 micrograms subcutaneously administered daily for 3 months; PTH(1-34)20 micrograms subcutaneously administered daily for 3 months
Other intervention name(s): PTHrP (1-36); PTHrP; PTHrP (1-36); PTHrP; PTH(1-34); Teriparatide (brand name: Forteo)
Intervention MeSH terms: Teriparatide; Hormones; Parathyroid Hormone; Parathyroid Hormone-Related Protein
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: osteoporosis; post-menopausal; bone anabolic agents