Parathyroid hormone (PTH) is a major regulator of bone and mineral metabolism. However, the manner by which PTH regulates the compartmentalization of trabecular and cortical bone remains unknown. Two diseases of PTH excess and deficiency, primary hyperparathyroidism (PHPT) and hypoparathyroidism (HypoPT), respectively, offer a rich repository of data that suggest roles for PTH not only with regard to circulating biochemical and densitometric indices of mineral metabolism, but perhaps more importantly, for fundamental histomorphometric and structural properties of trabecular and cortical bone. The goal of this research proposal is to apply an interdisciplinary approach to determine how PTH affects compartmentalization and microarchitecture of bone in subjects with PHPT or HypoPT before and after correction of the abnormal PTH state, either by normalization of PTH levels by parathyroidectomy (PHPT) or by administration of PTH (HypoPT). The changes that we expect to see at baseline and after correction of these abnormal PTH states will allow us to attribute, in a manner not previously shown, specific features of the skeleton tha are under the ultimate control of PTH. In addition, I will investigate whether the dual actions of PTH on cortical and trabecular bone can be shifted to a unimodal, osteoanabolic one by blocking its catabolic signaling pathway by denosumab, a specific blocker of receptor activator of nuclear factor kappa B ligand (RANKL). The quantitative tools that will be used in this research project include biochemical markers of bone turnover; bone mineral density by dual-energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT); Finite Element Analysis (FEA); and Individual Trabeculae Segmentation (ITS) analysis.

Public Health Relevance

Parathyroid hormone (PTH) is a major regulator of bone and mineral metabolism, yet the mechanisms by which PTH regulates compartmentalization and microarchitecture of bone remain unknown. The knowledge obtained in this study should help to better characterize the specific features of the skeleton that are under the ultimate control of PTH. This understanding may lead to the development of new therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK095944-04
Application #
8843422
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2012-07-01
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
4
Fiscal Year
2015
Total Cost
$183,568
Indirect Cost
$13,598
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
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
Cusano, Natalie E; Rubin, Mishaela R; Bilezikian, John P (2015) Parathyroid hormone therapy for hypoparathyroidism. Best Pract Res Clin Endocrinol Metab 29:47-55
Cusano, Natalie E; Rubin, Mishaela R; Bilezikian, John P (2015) PTH(1-84) replacement therapy for the treatment of hypoparathyroidism. Expert Rev Endocrinol Metab 10:5-13
Cusano, Natalie E; Bilezikian, John P (2014) Parathyroid hormone in the evaluation of hypercalcemia. JAMA 312:2680-1
Bandeira, Francisco; Cusano, Natalie E; Silva, Barbara C et al. (2014) Bone disease in primary hyperparathyroidism. Arq Bras Endocrinol Metabol 58:553-61
Cusano, N E; Rubin, M R; Irani, D et al. (2013) Use of parathyroid hormone in hypoparathyroidism. J Endocrinol Invest 36:1121-7
Cusano, Natalie E; Rubin, Mishaela R; McMahon, Donald J et al. (2013) Therapy of hypoparathyroidism with PTH(1-84): a prospective four-year investigation of efficacy and safety. J Clin Endocrinol Metab 98:137-44
Stein, Emily M; Silva, Barbara C; Boutroy, Stephanie et al. (2013) Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women. J Bone Miner Res 28:1029-40
Cusano, Natalie E; Maalouf, Naim M; Wang, Patty Y et al. (2013) Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab 98:2734-41
Cusano, Natalie E; Silverberg, Shonni J; Bilezikian, John P (2013) Normocalcemic primary hyperparathyroidism. J Clin Densitom 16:33-9