Osteoporosis is a major cause of morbidity and mortality in postmenopausal women. In an United States,, an estimated 13% to 18% of women have osteoporosis. The financial burden is substantial, with an estimated yearly cost of $10 billion in the United States alone. The lifetime risk for osteoporotic fractures in Caucasian women 50 years of age is about 30-40%. Between 13-19% of postmenopausal women who have a hip fracture die within the following year. We propose to use a combination of human calcitonin (hCT) and polymer-bound cathepsin K inhibitor (CKI) as a novel treatment of osteoporosis. The rationales for hCT use in osteoporosis therapy are the stimulation of osteoblasts, specific inhibition of bone resorption by osteoclasts, and prevention of fusion of osteoclast precursors. Clinical studies have shown that a significant gain in bone mass can be achieved by administration of CT. An osteoclast-specific cysteine proteinase, cathepsin K, plays a specialized role in the resorption of organic bone matrix. It was shown that cathepsin K inhibitors (CKI) are effective in reducing osteoclast-mediated bone resorption both in vitro and in vivo. The binding of CKI to a macromolecular carrier will change the mechanism of CKI internalization by osteoclasts from diffusion (CKI) to endocytosis (polymer-bound CKI). Consequently, the polymer-bound CKI will localize in the sealed zones of the ruffled border (resorption lacuna), i.e. exactly in the place where bone resorption mediated by cathepsin K occurs. We hypothesize that the combination of the actions of hCT and CKI will produce cures which cannot be achieved with hCT or CKI alone. Establishing an oral delivery system for hCT and CKI is of great importance because it is expected that for treatment of chronic disorders in non-life threatening situations, such as postmenopausal osteoporosis, parenteral administration will lead to poor patient compliance and thus restricted utility. hCT is an excellent candidate for the development of alternate delivery routes due to its size and wide therapeutic index. The size of CKIs will be modified with semitelechelic poly[(N-2- hydroxypropyl)methacrylamide] (ST-PHPMA) chains to achieve comparable hydrodynamic volumes of CT and of the ST-PHPMA-CK conjugate, which will simplify the design of the delivery system and have beneficial biological consequences. Novel hydrogels were designed in the first period of research; they contain azoaromatic crosslinks, susceptible to degradation by bacterial enzymes in the colon and hydrolyzable side-chains, which control the kinetics of swelling in the small intestine. The structure and properties of biodegradable hydrogels will be optimized. A new macromolecular CKI will be synthesized. Its efficacy will be evaluated in an osteoclast culture in vitro as well as on an animal model in vivo. The effect of combination therapy will be compared with individual therapies. The bioavailability of hCT and ST-PHPMA-CKI conjugates in rabbits and dogs using hydrogel based delivery devices and a penetration enhancer will be determined. The efficacy and biocompatibility of an hCT and CKI delivery device in an animal model of osteoporosis will be studied. Based on in vivo animal data criteria will be studied. Based on in vivo animal data criteria will be established for the design of an oral hCT and CKI delivery system for the treatment of postmenopausal osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
8R01EB000251-06
Application #
6490077
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Kelley, Christine A
Project Start
1995-04-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
6
Fiscal Year
2002
Total Cost
$187,200
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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