Current osteoporosis therapies such as calcitonin, estrogen and bisphosphonates are primarily antiresorptive agents. Parathyroid hormone (PTH) and its fragments have a potent anabolic effect, enhancing skeletal mass and quality of bone. PTH(1-31)NH2, an N-terminal fragment of PTH, has recently been shown to induce an osteogenic response comparable to that of intact PTH, but not the hypercalcemic response associated with long-term therapy with other forms of PTH. We hypothesize that orally delivered recombinant PTH(1-31)NH2 can be developed as an effective anabolic agent to treat osteoporosis, with enhanced patient compliance in chronic usage. Phase I of this proposal addresses the following specific aims: 1. Produce recombinant rhPTH(1-31)NH2 using our proprietary "direct expression" and amidation technologies; 2. Demonstrate by in vitro assays that the material is bioactive after purification; 3. Perform a preliminary pharmacokinetic oral study in rats with chemically synthesized peptide using our patented oral delivery formulation. During Phase II, we will carry out oral delivery studies in ovariectomized and intact rats to determine efficacy. Also, we will test an oral solid dosage form in dogs to demonstrate bioavailability, and carry out pilot studies in man designed as a basis for the clinical development of oral rhPTH(1-31)NH2
