The goal of this renewal application is to provide continued support for my mentoring program for junior faculty and fellows interested in patient- oriented research (POR). During my first K24, 2 junior faculty completed K awards, one received an R01 and 4 were awarded new K23s, a highly successful record. My future research goals are to conduct high quality POR elucidating cellular and structural mechanisms that underlie deficits in bone strength associated with postmenopausal osteoporosis, idiopathic osteoporosis (IOP) in premenopausal women, and other diseases associated with adverse effects on the skeleton. My mentoring goals are to use currently and newly funded projects to provide high quality mentoring and training for new clinical investigators in POR. During the grant, we defined consistent microarchitectural abnormalities of bone quality in women with IOP: thin cortices, trabecular loss, decreased connectivity, stiffness and mineralization. Despite some heterogeneity, the majority had low or normal remodeling. In the renewal, we will test the hypotheses that microarchitectural abnormalities in premenopausal women with IOP are related to abnormal formation, function or lifespan of bone cells, particularly osteoblasts and that PTH(1-34), a bone anabolic agent, can reverse the structural and dynamic abnormalities we have defined. We will use established and novel approaches to skeletal macro- and micro-imaging and cell biology that will provide novel insights into mechanisms of bone loss in IOP and a rational basis for its therapy. This proposal, as well as databases, biological specimens and imaging data from other currently and newly funded projects, will provide me with many opportunities to mentor junior investigators in POR and will also provide me with protected time to focus on training and mentoring. By investigating the causes and therapy of IOP, improving the health of young women with unexplained fractures, and permitting me to devote more time to POR and to training and mentoring junior faculty and fellows in POR, this proposal addresses several key missions of NIH.

Public Health Relevance

This project is relevant to public health because it investigates the structural and cellular bases of, and a pathphysiologically based therapy for, osteoporosis in otherwise healthy young women. The results will apply to other populations: young women with secondary causes of bone loss and postmenopausal osteoporosis. This project is an important training vehicle for young clinicians in fundamentals of patient-oriented research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24AR052665-10
Application #
8707368
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Chen, Faye H
Project Start
2005-09-05
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Wang, Ji; Stein, Emily M; Zhou, Bin et al. (2016) Deterioration of trabecular plate-rod and cortical microarchitecture and reduced bone stiffness at distal radius and tibia in postmenopausal women with vertebral fractures. Bone 88:39-46
Boutroy, Stephanie; Khosla, Sundeep; Sornay-Rendu, Elisabeth et al. (2016) Microarchitecture and Peripheral BMD are Impaired in Postmenopausal White Women With Fracture Independently of Total Hip T-Score: An International Multicenter Study. J Bone Miner Res 31:1158-66
Nishiyama, Kyle K; Pauchard, Yves; Nikkel, Lucas E et al. (2015) Longitudinal HR-pQCT and image registration detects endocortical bone loss in kidney transplantation patients. J Bone Miner Res 30:554-61
Stein, Emily M; Rogers, Halley; Leib, Alexa et al. (2015) Abnormal Skeletal Strength and Microarchitecture in Women With Celiac Disease. J Clin Endocrinol Metab 100:2347-53
Cohen, Adi; Kamanda-Kosseh, Mafo; Recker, Robert R et al. (2015) Bone Density After Teriparatide Discontinuation in Premenopausal Idiopathic Osteoporosis. J Clin Endocrinol Metab 100:4208-14
Misof, B M; Dempster, D W; Zhou, Hua et al. (2014) Relationship of bone mineralization density distribution (BMDD) in cortical and cancellous bone within the iliac crest of healthy premenopausal women. Calcif Tissue Int 95:332-9
Nishiyama, Kyle K; Cohen, Adi; Young, Polly et al. (2014) Teriparatide increases strength of the peripheral skeleton in premenopausal women with idiopathic osteoporosis: a pilot HR-pQCT study. J Clin Endocrinol Metab 99:2418-25
Stein, Emily M; Kepley, Anna; Walker, Marcella et al. (2014) Skeletal structure in postmenopausal women with osteopenia and fractures is characterized by abnormal trabecular plates and cortical thinning. J Bone Miner Res 29:1101-9
Iyer, Sapna P; Nikkel, Lucas E; Nishiyama, Kyle K et al. (2014) Kidney transplantation with early corticosteroid withdrawal: paradoxical effects at the central and peripheral skeleton. J Am Soc Nephrol 25:1331-41
Cohen, Adi; Stein, Emily M; Recker, Robert R et al. (2013) Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study. J Clin Endocrinol Metab 98:1971-81

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