The Impact of Glomerular Disorders on Bone Quality and Strength

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Impact of Glomerular Disorders on Bone Quality and Strength

Conditions
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Glomerular Disease, Bone Diseases, Metabolic, Bone Fracture

Intervention / Treatment
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* Radiation: Dual-energy X-ray absorptiometry
* Radiation: High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT)
* Other: Blood draw and Urine collection
* Other: Questionnaires


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for participants with glomerular disease: 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: First diagnostic kidney biopsy within 5 years of CureGN study enrollment Access to first kidney biopsy report and/or slides or not being interested in study participation. Males or females 5 to 55 years (premenopausal for women) Females must have a negative urine/serum pregnancy test 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) Consent/Parental/guardian permission (informed consent) and if appropriate, child assent Inclusion Criteria for healthy reference participants Males or females 5 to 55 years of age (premenopausal for women) Females must have a negative urine/serum pregnancy test Consent/Parental/guardian permission (informed consent) and if appropriate, child assent Exclusion Criteria for all participants Chronic Dialysis Solid organ transplantation Lower extremity amputations or non-ambulatory Malignancy requiring chemotherapy or metastatic to bone Metabolic bone disease (e.g., Paget's disease, primary hyperparathyroidism) Endocrinopathy (current hyperthyroidism or untreated hypothyroidism, Cushing's syndrome) Medical diseases (end stage liver disease, heart or lung disease, intestinal malabsorption) Those treated with bisphosphonates, teriparatide, calcitonin, selective estrogen receptor modulators, estrogen, or phenytoin in the past 12 months Previous bilateral wrist and tibia fractures Pregnant or lactating females Parents/guardians or participants who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney Disease, Bone Fracture