PTH has multiple, powerful effects on bone but its anabolic actions are poorly understood. In animals, intermittent PTH administration increases both cortical and trabecular bone mass and can prevent, or even reverse, bone loss. The anabolic effects of PTH on bone in humans have been less well studied. In particular the effects of intermittent PTH on cortical bone in humans are unclear and no studies have examined the roles that aging and/or prior bone loss play in the response to intermittent PTH. The former issue is important because cortical bone may be an independent determinant of fracture risk. The latter issue is important because the anabolic effect on trabecular bone in elderly osteoporotic people appears to plateau after about 1 year. We have previously demonstrated that intermittent PTH prevents spinal bone loss in young women rendered acutely estrogen-deficient with GnRH analog therapy. However, because GnRH analog therapy could only be continued for l year, we could not determine the effect of PTH on cortical bone in these women. This proposal will examine the effects of intermittent hPTH-( 1- 34) on bone mass and bone turnover in early menopausal women with normal bone density (BMD). The major aims of this proposal are 1) to determine whether intermittent PTH prevents both cortical and trabecular bone loss in early menopausal women. 2) to assess whether aging and/or prior bone loss is an important determinant of the response to intermittent PTH. and 3) to identify factors that predict the skeletal response to long- term intermittent PTH. 75 early menopausal women with normal BMD will be randomly assigned to treatment with hPTH-( 1-34) 40 ug/day: hPTH-( 1-34) 20 ug/day: or placebo. BMD at sites reflecting cortical and trabecular bone, biochemical markers of bone formation osteocalcin and PICP) and resorption (urinary NTx and DPD) blood cytokines (IL-6, IL-1beta, and TNFalpha), and IGF-I will be monitored at regular intervals for 3 years. The model of early menopausal women with normal BMD is more homogeneous than populations of elderly women with osteoporosis so that studies of PTH in this group are more likely to have interpretable results. Two doses of PTH will be used to determine whether a lower dose can selectively increase bone formation compared to a higher dose which is known to increase bone formation and resorption. By comparing responses in these women with those of elderly osteoporotic women from Dr. Neer's protocol (who receive an identical dose of PTH) we will be able to assess the impact of aging and/or prior bone loss on the skeletal response to PTH. The ability to integrate these proposals in a major advantage of the SCOR structure.

Project Start
1998-09-01
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1998
Total Cost
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

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