(Taken from the application): Once-daily PTH injections increase bone mass and strength more than other treatments in osteoporotic women and men, but rarely cure osteoporosis. Daily PTH injections increase bone resorption as well as formation, so combining them with an anti-resorptive agent should enhance the effect on bone mass. Experiments elsewhere in animals and humans failed to confirm this expectation, but their design made interpretation difficult, so we are treating osteoporotic women and men with PTH, alendronate, or both, serially assessing bone formation and resorption and BMD of multiple sites. This also tests whether PTH must increase bone resorption in order to increase bone formation and BMD in humans, or whether a bisphosphonate interferes with PTH-mediated increases in bone formation. At the end of this experiment we will evaluate skeletal and renal responses to sc PTH, and to a 12-hour iv PTH infusion, stop PTH but not alendronate, follow the patients for a year, and then re-evaluate BMD and acute responses to sc and iv PTH. This will test whether acute renal and early skeletal responses to PTH are restored by a 12 month interval without PTH administration, and whether BMD increases after stopping PTH (because bone remodeling decreases) or whether (as in animals) BMD decreases rapidly after stopping PTH, unless an anti-resorptive agent is administered. We will then treat every patient with PTH for a year (not changing any alendronate treatment), to test whether daily sc PTH's effects on bone turnover are restored by a 12 month interval without PTH administration, with additional increases in BMD. In osteoporotic animals and humans, PTH?s therapeutic effects are limited by a PTH resistance that slowly develops during prolonged daily PTH administration. We will test whether this PTH resistance reflects decreased blood levels of the injected peptide, delayed development of anti-PTH antibodies, down-regulation of PTH-receptors and receptor-mediated activation of adenylate cyclase (in an accessible PTH target organ, the kidney), or a decrease in PTH?s early effects on bone formation (the suppression of bone formation and stimulation of bone resorption seen during a 12-hour intravenous PTH infusion). Finally, we will test in a new set of patients whether PTH resistance can be overcome by serial increases in the administered PTH dose.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
2P50AR044855-05
Application #
6495968
Study Section
Special Emphasis Panel (ZAR1)
Project Start
1997-09-22
Project End
2005-08-31
Budget Start
Budget End
Support Year
5
Fiscal Year
2001
Total Cost
$282,097
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Yu, Elaine W; Neer, Robert M; Lee, Hang et al. (2011) Time-dependent changes in skeletal response to teriparatide: escalating vs. constant dose teriparatide (PTH 1-34) in osteoporotic women. Bone 48:713-9
Finkelstein, Joel S; Wyland, Jason J; Lee, Hang et al. (2010) Effects of teriparatide, alendronate, or both in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 95:1838-45
Finkelstein, Joel S; Wyland, Jason J; Leder, Benjamin Z et al. (2009) Effects of teriparatide retreatment in osteoporotic men and women. J Clin Endocrinol Metab 94:2495-501
Leder, Benjamin Z; Neer, Robert M; Wyland, Jason J et al. (2009) Effects of teriparatide treatment and discontinuation in postmenopausal women and eugonadal men with osteoporosis. J Clin Endocrinol Metab 94:2915-21
Finkelstein, Joel S; Leder, Benjamin Z; Burnett, Sherri-Ann M et al. (2006) Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men. J Clin Endocrinol Metab 91:2882-7
Kobayashi, Tatsuya; Kronenberg, Henry M; Foley, John (2005) Reduced expression of the PTH/PTHrP receptor during development of the mammary gland influences the function of the nipple during lactation. Dev Dyn 233:794-803
Miao, Dengshun; He, Bin; Jiang, Yebin et al. (2005) Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest 115:2402-11
Inada, Masaki; Wang, Yingmin; Byrne, Michael H et al. (2004) Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci U S A 101:17192-7
Kuznetsov, Sergei A; Riminucci, Mara; Ziran, Navid et al. (2004) The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J Cell Biol 167:1113-22
Chiusaroli, R; Maier, A; Knight, M C et al. (2003) Collagenase cleavage of type I collagen is essential for both basal and parathyroid hormone (PTH)/PTH-related peptide receptor-induced osteoclast activation and has differential effects on discrete bone compartments. Endocrinology 144:4106-16

Showing the most recent 10 out of 17 publications