Clinical trial NCT02440581: Renal Osteodystrophy: An Individual Management Approach
Official title: Renal Osteodystrophy: A Fresh Approach
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Kidney Failure, Chronic
Lead sponsor: University of Kentucky
Sponsor class: OTHER
Collaborators: name: Wright State University
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2015-05-12
Enrollment: 141
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 chronic kidney disease (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 in 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 National Institute of Diabetes and Digestive and Kidney Diseases' mission of disseminating science-based information to improve the health and quality of life for patients with endocrine, metabolic and kidney diseases.


Eligibility criteria: Inclusion Criteria:

* Aged 21 years or older;
* Chronic maintenance dialysis of at least 3 months' duration;
* Osteoporotic by DXA of either spine or total hip (Women: post-menopausal or age ≥ 50 with T-score ≤ -2.5; Men: age ≥ 50 with T-score ≤ -2.5; All others, Z-score ≤ -2.5);
* Mental competence;
* Willingness to participate in the study;
* Normal serum calcium.

Exclusion Criteria:

* Pregnancy or breast feeding;
* Incarceration;
* Systemic illnesses or organ diseases that may affect bone (except type 1 or type 2 diabetes mellitus);
* Clinical condition that may limit study participation (e.g., unstable angina, respiratory distress, infections).
* Chronic alcoholism and/or drug addiction;
* Known Paget 's disease of bone;
* Prior external beam or implant radiation therapy involving the skeleton;
* More than 3 computed tomography (CT) scans in the prior 12 months (to avoid excessive radiation exposure);
* Participation in a study of an investigational drug during the past 90 days;
* Planning to move out of the area within 1 year of the study;
* On active transplant list;
* BMD t-score of the radius less than -3.5 by DXA (to avoid the known potential negative effects of teriparatide treatment on BMD of the radius);
* Planned or anticipated oral surgery within the next 12 months;
* Inability to stand or sit upright for at least 30 minutes;
* Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia;
* Treatment within last 6 months with drugs that may affect bone metabolism including bisphosphonates and teriparatide (except for treatment with calcitriol, vitamin D analogs and/or calcimimetics);
* Current treatment with medicines containing digoxin or warfarin;
* Calcidiol level below the normal range. (The current routine clinical practice in our dialysis clinics is to check calcidiol status twice yearly and supplement with vitamin D according to serum calcidiol levels. It is therefore unlikely that a substantial number of patients will be excluded due to this exclusion criterion.)

Primary outcomes:
measure: Change in Quantitative Computed Tomography (QCT) Bone Mineral Density of the Hip
timeFrame: One Year (at baseline and one year)
Secondary outcomes:
measure: Change in Coronary Artery Calcifications by Multiple Detector Computed Tomography (MDCT)
timeFrame: One year (at baseline and one year)
measure: Change in Serum Biochemical Bone Markers of Bone Activity - Parathyroid Hormone (PTH)
timeFrame: 1 Year (at baseline and one year)
measure: Change in Serum Biochemical Bone Markers of Bone Activity - Bone-specific Alkaline Phosphatase (BSAP)
timeFrame: 1 year (at baseline and one year)
measure: Change in Serum Biochemical Bone Markers of Bone Activity - Fibroblast Growth Factor 23 (FGF23)
timeFrame: 1 Year (at baseline and 1 year)
Other outcomes:
Locations:
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
Study officials:
affiliation: University of Kentucky
name: Hartmut Malluche, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hara T, Hijikata Y, Matsubara Y, Watanabe N. Pharmacological interventions versus placebo, no treatment or usual care for osteoporosis in people with chronic kidney disease stages 3-5D. Cochrane Database Syst Rev. 2021 Jul 7;7(7):CD013424. doi: 10.1002/14651858.CD013424.pub2.