Hypoparathyroidism is an uncommon human skeletal disorder in which parathyroid hormone (PTH) is markedly decreased or absent from the circulation. It is due primarily to surgical removal of all parathyroid tissue or autoimmune destruction of the parathyroid glands. The absence of PTH leads to a reduction in the serum calcium concentration that can be asymptomatic or associated with symptoms of hypocalcemia. PTH deficiency also leads to major abnormalities in biochemical, densitometric, histomorphometric, biomechanical and cellular properties of the skeleton. Over the past 5 years of funding, we have gained insights into these aspects of the skeleton that are regulated by PTH. This proposal seeks to continue and to expand this investigation in order to gain more complete understanding of PTH's skeletal actions. To this end, in addition to completing our studies of hypoparathyroidism, we will apply our experimental approach to another human skeletal disorder, primary hyperparathyroidism (PHPT), a disorder of excessive PTH. We will use a cotemporaneous experimental design to investigate these two completely different parathyroid disorders, which represent opposite ends of the PTH insufficiency/excess spectrum. The model achieves greater significance because we will correct both PTH disorders, either by replacement of PTH (hypoparathyroidism) or by removal of excess PTH by parathyroid surgery (PHPT). By studying skeletal features before and after correction of states of PTH deficiency or excess, we can assign specific skeletal properties to this molecule. State-of-the-art approaches include methods to assess quantitative structural and dynamic features of the skeleton: dual energy X-ray absorptiometry, quantitative peripheral and central computed tomography (including high resolution pQCT, finite element analysis, Individual Trabecular Segmentation analysis, voxel- based QCT) and measurement of skeletal indices from analysis of iliac crest bone biopsies (histomorphometry, 5CT, synchrotron-based 5CT, quantitative back scattered electron imaging, and Fourier Transform Infrared Spectroscopy). In addition, bone turnover markers and circulating osteoblast precursor cells will be measured. The new knowledge from this proposal will have far wider implications than those associated with an uncommon disease. Rather, we anticipate our results will have far broader implications, including greater understanding both of the normal control of the skeleton by PTH and of the anabolic activity of PTH in the treatment of postmenopausal osteoporosis.

Public Health Relevance

This project is designed to gain new knowledge of the means by which parathyroid hormone, a key regulator of skeletal health, helps to keep bones strong.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069350-08
Application #
8301015
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (03))
Program Officer
Malozowski, Saul N
Project Start
2004-12-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$605,053
Indirect Cost
$199,565
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Rubin, Mishaela R; Cusano, Natalie E; Fan, Wen-Wei et al. (2016) Therapy of Hypoparathyroidism With PTH(1-84): A Prospective Six Year Investigation of Efficacy and Safety. J Clin Endocrinol Metab 101:2742-50
Cusano, Natalie E; Nishiyama, Kyle K; Zhang, Chengchen et al. (2016) Noninvasive Assessment of Skeletal Microstructure and Estimated Bone Strength in Hypoparathyroidism. J Bone Miner Res 31:308-16
Misof, Barbara M; Roschger, Paul; Dempster, David W et al. (2016) PTH(1-84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization. J Bone Miner Res 31:180-9
Rubin, Mishaela R; Zwahlen, Alexander; Dempster, David W et al. (2016) Effects of Parathyroid Hormone Administration on Bone Strength in Hypoparathyroidism. J Bone Miner Res 31:1082-8
Zhou, Bin; Zhang, Zhendong; Wang, Ji et al. (2016) In Vivo Precision of Digital Topological Skeletonization Based Individual Trabecula Segmentation (ITS) Analysis of Trabecular Microstructure at the Distal Radius and Tibia by HR-pQCT. Pattern Recognit Lett 76:83-89
Cusano, Natalie E; Rubin, Mishaela R; Bilezikian, John P (2015) Parathyroid hormone therapy for hypoparathyroidism. Best Pract Res Clin Endocrinol Metab 29:47-55
Silva, Barbara C; Bilezikian, John P (2015) Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol 22:41-50
Cusano, Natalie E; Rubin, Mishaela R; McMahon, Donald J et al. (2014) PTH(1-84) is associated with improved quality of life in hypoparathyroidism through 5 years of therapy. J Clin Endocrinol Metab 99:3694-9
Cusano, Natalie E; Rubin, Mishaela R; Zhang, Chiyuan et al. (2014) Parathyroid hormone 1-84 alters circulating vascular endothelial growth factor levels in hypoparathyroidism. J Clin Endocrinol Metab 99:E2025-8
Cusano, N E; Rubin, M R; Irani, D et al. (2013) Use of parathyroid hormone in hypoparathyroidism. J Endocrinol Invest 36:1121-7

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