The Impact of Glomerular Disorders on Bone Quality and Strength (BoneGN)

The primary objectives of this study are to: (1) determine the impact of glomerular disease on bone strength and (2) investigate the pathophysiologic underpinnings of impaired bone strength in glomerular disease.

Study Overview

• Status: Recruiting
• Conditions: Bone Diseases, Metabolic; Glomerular Disease; Bone Fracture
• Intervention / Treatment: Radiation: Dual-energy X-ray absorptiometry; Radiation: High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT); Other: Blood draw and Urine collection; Other: Questionnaires

Detailed Description

Children and adults with glomerular disease have unique and potentially modifiable risk factors for compromised bone health, but our current understanding of skeletal fragility in glomerular disease is lacking. In the first large population-based cohort study, we recently found that primary glomerular disease was independently associated with an increased risk of incident fracture, and that hip fracture risk was >2-fold greater in patients younger vs. older than 40 years of age. Mechanisms that drive increased fracture risk in glomerular disease are not clear but likely multifactorial. Our prior work demonstrated that glomerular disease is associated with disturbances in vitamin D and mineral metabolism, in addition to and exacerbated by reduced kidney function.

Patients with glomerular disease are also exposed to medications which may negatively impact bone health, most notably high-dose and long-term glucocorticoid therapy. Identifying modifiable factors that compromise bone strength will facilitate the development of strategies to reduce fractures and other skeletal complications across the life course. The proposed multi-center study will leverage the infrastructure of the NIH-funded Cure Glomerulopathy (CureGN) prospective cohort study and the resources of two health systems with expertise in state-of-the-art high-resolution bone imaging methods, to conduct the first prospective, longitudinal study to assess determinants of impaired bone quality and strength in glomerular disease.

• Study Type: Observational
• Enrollment (Anticipated): 270

Contacts and Locations

• Study Contact: Name: Maria A. Aponte; Phone Number: (212) 342-4678; Email: maa2308@cumc.columbia.edu
• Study Contact Backup: Name: Thomas L. Nickolas, MD; Phone Number: (212) 305-3273; Email: tln2001@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Maria A. Aponte; Phone Number: 212-342-4678; Email: maa2308@cumc.columbia.edu
      • Principal Investigator: Thomas L. Nickolas, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • The Children's Hospital of Philadelphia
      • Contact: Erin Doherty; Phone Number: 267-600-6233; Email: dohertye@email.chop.edu
      • Principal Investigator: Michelle R. Denburg, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 53 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Prospective cohort study of 150 CureGN participants (100 adults/50 children) and 120 age-, sex-, race-, and body mass index-matched healthy reference participants who will be evaluated at baseline and 12 months.

The CureGN DCC at Arbor Research will identify CureGN participants eligible for inclusion. Recruitment of healthy participants will also occur by leveraging the services of the CHOP Recruitment Enhancement Core (REC), Pediatric Research Consortium (PeRC) and the RecruitMe tool provided by the Clinical Trials Office at CUMC. Healthy adult controls will be recruited from patients who receive outpatient care within the Penn Primary Care Networks, Penn employees and students, an extensive database of individuals who have participated in prior research studies at Penn and through local advertising on the Penn campus.

Description

Inclusion Criteria for participants with glomerular disease:

1. CureGN participant or CureGN Eligible

   CureGN eligible is defined as having a diagnosis of Glomerulonephropathy (GN). Patients would otherwise be enrolled in be in CureGN study, except for lacking a minor entry criteria, such as:

   1. First diagnostic kidney biopsy within 5 years of CureGN study enrollment
   2. Access to first kidney biopsy report and/or slides or not being interested in study participation.
2. Males or females 5 to 55 years (premenopausal for women)
3. Females must have a negative urine/serum pregnancy test
4. Stable doses of nutritional vitamin D or active vitamin D therapy for at least 3 months before enrollment ((if on either form of Vitamin D)
5. Consent/Parental/guardian permission (informed consent) and if appropriate, child assent

Inclusion Criteria for healthy reference participants

1. Males or females 5 to 55 years of age (premenopausal for women)
2. Females must have a negative urine/serum pregnancy test
3. Consent/Parental/guardian permission (informed consent) and if appropriate, child assent

Exclusion Criteria for all participants

1. Chronic Dialysis
2. Solid organ transplantation
3. Lower extremity amputations or non-ambulatory
4. Malignancy requiring chemotherapy or metastatic to bone
5. Metabolic bone disease (e.g., Paget's disease, primary hyperparathyroidism)
6. Endocrinopathy (current hyperthyroidism or untreated hypothyroidism, Cushing's syndrome)
7. Medical diseases (end stage liver disease, heart or lung disease, intestinal malabsorption)
8. Those treated with bisphosphonates, teriparatide, calcitonin, selective estrogen receptor modulators, estrogen, or phenytoin in the past 12 months
9. Previous bilateral wrist and tibia fractures
10. Pregnant or lactating females
11. Parents/guardians or participants who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
BoneGN participants; Participants who have already been recruited into the CureGN study, or meet its criteria.	Radiation: Dual-energy X-ray absorptiometry; DXA whole body, hip, spine, and radius at baseline, and 12-month visit.; Other Names: Bone density; Radiation: High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT); HR-pQCT of the radius and tibia at baseline, and 12-month visit.; Other Names: HR-pQCT; Other: Blood draw and Urine collection; The blood draw can be completed +/- 3 weeks from baseline or 12-month visit.; Other: Questionnaires; Questionnaires regarding fracture history, physical activity and dietary intake at baseline, and 12-month visit.
Healthy subjects; A reference population of healthy subjects who are age- sex- BMI-matched to the CureGN study participants.	Radiation: High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT); HR-pQCT of the radius and tibia at baseline, and 12-month visit.; Other Names: HR-pQCT; Other: Questionnaires; Questionnaires regarding fracture history, physical activity and dietary intake at baseline, and 12-month visit.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in radius bone strength (failure load)	HR-pQCT will be used to assess bone microarchitecture and generate micro-finite element analysis (µFEA)-based estimates of bone strength.	Baseline and 12 months
Change in tibia bone strength (failure load)	HR-pQCT will be used to assess bone microarchitecture and generate micro-finite element analysis (µFEA)-based estimates of bone strength.	Baseline and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radius mid-shaft failure load	Measured with HR-pQCT	Up to 12 months
Tibia mid-shaft failure load	Measured with HR-pQCT	Up to 12 months
Cortical density of radius	Measured with HR-pQCT	Up to 12 months
Cortical density of tibia	Measured with HR-pQCT	Up to 12 months
Cortical thickness of radius	Measured with HR-pQCT	Up to 12 months
Cortical thickness of tibia	Measured with HR-pQCT	Up to 12 months
Areal bone mineral density (aBMD) at the hip	Hip (total and femoral neck) is measured with dual-energy x-ray absorptiometry (DXA)	Up to 12 months
aBMD at forearm	Forearm (one-third and ultradistal radius) is measured with DXA	Up to 12 months
aBMD at lumbar spine	Lumbar spine is measured with DXA	Up to 12 months
Bone mineral content at the hip	Hip (total and femoral neck) is measured with dual-energy x-ray absorptiometry (DXA)	Up to 12 months
Bone mineral content at forearm	Forearm (one-third and ultradistal radius) is measured with DXA	Up to 12 months
Bone mineral content at lumbar spine	Lumbar spine is measured with DXA	Up to 12 months

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Thomas L. Nickolas, MD, Columbia University

Publications and helpful links

General Publications

• Webster AC, Nagler EV, Morton RL, Masson P. Chronic Kidney Disease. Lancet. 2017 Mar 25;389(10075):1238-1252. doi: 10.1016/S0140-6736(16)32064-5. Epub 2016 Nov 23.
• Saran R, Robinson B, Abbott KC, Agodoa LY, Albertus P, Ayanian J, Balkrishnan R, Bragg-Gresham J, Cao J, Chen JL, Cope E, Dharmarajan S, Dietrich X, Eckard A, Eggers PW, Gaber C, Gillen D, Gipson D, Gu H, Hailpern SM, Hall YN, Han Y, He K, Hebert H, Helmuth M, Herman W, Heung M, Hutton D, Jacobsen SJ, Ji N, Jin Y, Kalantar-Zadeh K, Kapke A, Katz R, Kovesdy CP, Kurtz V, Lavalee D, Li Y, Lu Y, McCullough K, Molnar MZ, Montez-Rath M, Morgenstern H, Mu Q, Mukhopadhyay P, Nallamothu B, Nguyen DV, Norris KC, O'Hare AM, Obi Y, Pearson J, Pisoni R, Plattner B, Port FK, Potukuchi P, Rao P, Ratkowiak K, Ravel V, Ray D, Rhee CM, Schaubel DE, Selewski DT, Shaw S, Shi J, Shieu M, Sim JJ, Song P, Soohoo M, Steffick D, Streja E, Tamura MK, Tentori F, Tilea A, Tong L, Turf M, Wang D, Wang M, Woodside K, Wyncott A, Xin X, Zang W, Zepel L, Zhang S, Zho H, Hirth RA, Shahinian V. US Renal Data System 2016 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2017 Mar;69(3 Suppl 1):A7-A8. doi: 10.1053/j.ajkd.2016.12.004. No abstract available. Erratum In: Am J Kidney Dis. 2017 May;69(5):712.
• Floege J, Amann K. Primary glomerulonephritides. Lancet. 2016 May 14;387(10032):2036-48. doi: 10.1016/S0140-6736(16)00272-5. Epub 2016 Feb 25.
• Clark SL, Denburg MR, Furth SL. Physical activity and screen time in adolescents in the chronic kidney disease in children (CKiD) cohort. Pediatr Nephrol. 2016 May;31(5):801-8. doi: 10.1007/s00467-015-3287-z. Epub 2015 Dec 18.
• Denburg MR, Kumar J, Jemielita T, Brooks ER, Skversky A, Portale AA, Salusky IB, Warady BA, Furth SL, Leonard MB. Fracture Burden and Risk Factors in Childhood CKD: Results from the CKiD Cohort Study. J Am Soc Nephrol. 2016 Feb;27(2):543-50. doi: 10.1681/ASN.2015020152. Epub 2015 Jul 2.
• Phan V, Blydt-Hansen T, Feber J, Alos N, Arora S, Atkinson S, Bell L, Clarson C, Couch R, Cummings EA, Filler G, Grant RM, Grimmer J, Hebert D, Lentle B, Ma J, Matzinger M, Midgley J, Pinsk M, Rodd C, Shenouda N, Stein R, Stephure D, Taback S, Williams K, Rauch F, Siminoski K, Ward LM; Canadian STOPP Consortium. Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome. Osteoporos Int. 2014 Feb;25(2):627-37. doi: 10.1007/s00198-013-2466-7. Epub 2013 Aug 16.
• Alem AM, Sherrard DJ, Gillen DL, Weiss NS, Beresford SA, Heckbert SR, Wong C, Stehman-Breen C. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000 Jul;58(1):396-9. doi: 10.1046/j.1523-1755.2000.00178.x.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2019
• Primary Completion (Anticipated): December 15, 2023
• Study Completion (Anticipated): December 15, 2024

Study Registration Dates

• First Submitted: August 24, 2020
• First Submitted That Met QC Criteria: August 24, 2020
• First Posted (Actual): August 27, 2020

Study Record Updates

• Last Update Posted (Actual): April 15, 2022
• Last Update Submitted That Met QC Criteria: April 8, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Kidney Disease; Bone Fracture
• Additional Relevant MeSH Terms: Wounds and Injuries; Musculoskeletal Diseases; Fractures, Bone; Bone Diseases; Bone Diseases, Metabolic; Metabolic Diseases
• Other Study ID Numbers: AAAS0922; R01DK119266 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Only investigators and study team members that have completed appropriate institutional review board (IRB) training/approval are eligible to collect and work on information collected from this study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No