A MECHANISTIC STUDY OF SKELETAL ACTIONS OF 1-34hPTH
Principal Investigator: R Lindsay
Abstract: The introduction of 1-34rhPTH (teriparatide) as a treatment for osteoporosis has been a major advance. Currently, the use of 1-34rhPTH is limited to 2 years of daily subcutaneous injections. PTH stimulates bone formation and secondarily bone remodeling, effects which dissipate by about 2 years. Little is known about the cellular mechanisms by which PTH produces its effects. This application seeks to evaluate the early (7 week) and later (7.5 month) responses to PTH in cancellous, and cortical bone, as well as on the inner (endocortex) and outer (periosteal) surfaces of bone from the iliac crest. We will use our unique quadruple tetracycline labeling system that allows us to obtain information about dynamic indices of bone formation at 2 time points using only a single biopsy. By giving 1 pair of tetracycline labels before initiating PTH and the second pair 1 month after starting PTH, we can use each subject as her own control, thereby markedly reducing the well known variability across subjects and within subjects when analyzing duplicate biopsies. We will examine the early formation response of the skeleton to PTH at 7 weeks when there is little stimulation of resorption, and later at 7.5 months, a time point that coincides with maximal stimulation of remodeling as assessed by biochemical markers. We will also seek to determine if delivering PTH cyclically (3 months on/3 months off) can separate the early formation response from the remodeling response, and provide repetitive stimuli to new bone formation. Using the quadruple labeling system with biopsies at 7 weeks and 7.5 months in women receiving cyclic PTH, we hypothesize that there will be less remodeling during the off phase and a second boost to formation that we will detect at 7.5 months. Finally, we will address an important clinical question, by examining the skeletal response to PTH (daily and cyclic) after 24 months in subjects either naive to treatment or on alendronate for at least 1 year, and who are in a new steady state. These data should provide important information on the mechanism of action of PTH at the cellular level, allow for a better understanding of the interaction of an antiresoptive agent and an anabolic agent, and delineate a more efficient approach to the clinical use of PTH.
Funding Period: 2005-09-22 - 2010-05-31
more information: NIH RePORT
- Three dimensional cancellous bone structure in hypoparathyroidismMishaela R Rubin
Metabolic Bone Diseases Unit, Department of Medicine, College of Physicians and Surgeons, Columbia University New York, NY, USA
Bone 46:190-5. 2010..The effect of these structural changes on bone strength remains to be determined...
- Effects of cyclic vs. daily treatment with human parathyroid hormone (1-34) on murine bone structure and cellular activityAkiko Iida-Klein
Helen Hayes Hospital, Regional Bone Center, West Haverstraw, NY 10993, USA
Bone 40:391-8. 2007..A cyclic PTH regimen was as effective as a daily regimen in improving cancellous and cortical bone microarchitecture and cellular activity in the murine vertebra...
- Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human iliumRobert Lindsay
Clinical Research Center, Helen Hayes Hospital, West Haverstraw, NY 10993, USA
J Bone Miner Res 22:495-502. 2007..Enhanced bone formation was associated with an increase in osteoblast apoptosis...
- Preserved three-dimensional cancellous bone structure in mild primary hyperparathyroidismD W Dempster
Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York 10993, USA
Bone 41:19-24. 2007..Also of note, there was no difference in any 3-dimensional index between women and men with PHPT. We conclude that three-dimensional, cancellous bone microarchitecture is preserved in patients with mild primary hyperparathyroidism...