Renal osteodystrophy (ROD) represents the bone histologic abnormalities resulting from loss of renal function. It starts early during the loss of kidney function and is seen in virtually all chronic end stage kidney disease patients on dialysis (CKD-5D). A major component of ROD is bone loss leading to CKD-associated osteoporosis. Debilitating hip fractures occur in patients with CKD at a rate 4.4 times higher than in the general population, with associated high costs, morbidity and an annual mortality of 64%. CKD osteoporosis is distinctly different from post-menopausal osteoporosis. Presently, no uniformly accepted CKD osteoporosis treatment protocol exists because of challenges related to racially specific bone turnover states. Therefore, most physicians are reluctant to treat this disorder despite the profound impact on health and quality of life, and its association with vascular calcifications. These vascular calcifications confer an increased risk for cardiovascular events which are the major cause of the over 20% annual mortality rate in CKD-5D patients. The goal of the proposed controlled randomized study is to test the concept that CKD osteoporosis can be successfully treated when treatment is individualized by patients' turnover status. The study will demonstrate that reversal of bone loss can be achieved by increasing bone formation in low turnover patients, and by reducing bone resorption in normal or high turnover patients.
A second aim of this study is to provide new information whether these treatments will also retard progression of vascular calcifications. Blood tests measuring FGF23, indicators of Wnt pathway activity, bone resorption and formation will be followed to understand potential mechanisms and to evaluate their usefulness for prediction of changes in bone mass and vascular calcifications. CKD-5D patients with established osteoporosis will be enrolled into one of two treatment arms based on bone turnover status. Each arm will be adaptively randomized by race, age and gender into treatment or control groups. In the low turnover arm, teriparatide combined with cinacalcet will be given, and in the normal or high turnover arm, alendronate will be administered. Bone mineral density will be measured at baseline and after one year of treatment by quantitative computed tomography. Calcifications of the coronaries, aorta and heart valves will also be measured at the same times by multi-detector computed tomography. If this proof-of-concept study is successful, it will offer a heretofore unavailable treatment for osteoporosis i CKD-5D patients thus changing the prevailing clinical practice paradigm. This will provide immediate benefit to CKD patients by reducing fracture risk, bone pain, and cardiovascular risk, while greatly improving their quality of life. These improvements will also convey major socioeconomic benefits by decreasing the high associated treatment costs. The proposed study is highly relevant to the NIDDK's mission of disseminating science-based information to improve the health and quality of life for patients with endocrine, metabolic and kidney diseases.

Public Health Relevance

More than 30 million people in the United States have chronic kidney disease and this research will provide proof of concept for a novel osteoporosis treatment regimen for patients with late-stage chronic kidney disease. There is currently no established treatment regimen for chronic kidney disease associated osteoporosis even though it is associated with early and frequent debilitating hip fractures which require costly surgery, result in reduced quality of life, high mortality and impose an enormous socioeconomic burden. The study will also provide information whether this novel treatment will reduce the relentless progression of vascular calcifications in these patients, which have been linked to heart attack, cardiac arrest and stroke resulting in an annual mortality that exceeds many cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080770-08
Application #
9529631
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Roy, Cindy
Project Start
2008-04-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
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Agapova, Olga A; Fang, Yifu; Sugatani, Toshifumi et al. (2016) Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease. Kidney Int 89:1231-43
Anaya, Paul; Blomquist, Gustav A; Davenport, Daniel L et al. (2016) Coronary artery calcification in CKD-5D ?patients is tied to adverse cardiac function ?and increased mortality?. Clin Nephrol 86 (2016):291-302
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Haarhaus, Mathias; Monier-Faugere, Marie-Claude; Magnusson, Per et al. (2015) Bone alkaline phosphatase isoforms in hemodialysis patients with low versus non-low bone turnover: a diagnostic test study. Am J Kidney Dis 66:99-105
Malluche, Hartmut H; Blomquist, Gustav; Monier-Faugere, Marie-Claude et al. (2015) High Parathyroid Hormone Level and Osteoporosis Predict Progression of Coronary Artery Calcification in Patients on Dialysis. J Am Soc Nephrol 26:2534-44
Fang, Yifu; Ginsberg, Charles; Seifert, Michael et al. (2014) CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol 25:1760-73

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